Nucleotide analogs

ABSTRACT

Nucleotide analogs characterized by the presence of an amidate linked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or ester bond that is hydrolyzed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for their synthesis and use are described.

CROSS REFERENCED TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/778,856, filedFeb. 13, 2004, now abandoned, which is a continuation of U.S. Ser. No.09/801,164, filed Mar. 7, 2001, now abandoned, which is a continuationof U.S. Ser. No. 09/247,497, filed Feb. 10, 1999, now U.S. Pat. No.6,225,460, which is a continuation of U.S. Ser. No. 09/071,420, filedMay 1, 1998, now abandoned, which is a divisional application of Ser.No. 08/617,849, filed May 6, 1996, now U.S. Pat. No. 5,798,340, which isa continuation of PCT/US94/10539, filed Sep. 16, 1994, which is acontinuation-in-part application of U.S. Ser. No. 08/193,341, filed Feb.8, 1994, now abandoned, which is a continuation-in-part of U.S. Ser. No.08/123,483, filed Sep. 17, 1993, now U.S. Pat. No. 5,656,745.

BACKGROUND OF THE INVENTION

The present invention relates to novel nucleotide analog amidates andesters, their pharmaceutically acceptable acid addition salts, a processfor their production, and to their use. The nucleotides of the presentinvention exhibit antitumor/antineoplastic activity, a broad spectrum ofantimicrobial activity and certain other desirable activities.

Compounds related to the nucleotide analogs of the present invention maybe found in: U.S. Pat. Nos. 5,043,339, 5,108,994 and 5,166,198; EP 206459; EP 253 412; EP 269 947; EP 270 885; EP 319 228; EP 343 133; EP 398231; EP 404 296; EP 465 297; EP 468 119; EP 468 866; EP 479 640; EP 481214; EP 494 370; EP 531 597; PCT/GB91/01171; PCT/US92/01020;PCT/US92/05208; WO 91/19721; Bronson et al, Bioorg Medicinal Chem Lett(1992) 2:685-690; Bronson et al, J Med Chem, (1989) 32:1457-1463;Bronson et al, Nucleotide Analogs as Antiviral Agents, ACS SymposiumSeries 401, J. C. Martin, Ed., p. 72-87, American Chemical Society,Washington, D.C. (1989); Colla, et al, J Med Chem (1983) 26:602-604;Curley, et al, Antiviral Res (1990) 14:345-356; De Clercq, et al,Nature, (1986) 323:464-467; Farrow, et al, J Med Chem (1990)33:1400-1406; Farquhar, et al, J. Pharm Sci (1983) 72:324-325; Freed, etal, Biochem Pharmacol (1989) 19:3193-3198; Freeman, et al, J Med Chem(1992) 35:3192-3196; Gabrielsen, B., et al, Antiviral Res Suppl I (1992)17:149; Gumport, et al, Proc Natl Acad Sci (1971) 2559-2563; Juodka, etal, Coll Czech Chem Comnmun (1974) 39:963-968; Kim, et al, BioorgMedicinal Chem Lett (1992) 2:367-370; Kim, et al, Tet Lett (1992)33:25-28; Kim, et al, J Med Chem (1990) 33:1207-1213; Kumar, et al, JMed Chem (1990) 33:2368-2375; McGuigan, et al, Antiviral Chem Chemother(1993) 4:97-101; McGuigan, et al, Antiviral Res (1991) 15:255-263;Rosenberg, et al, Coll Czech Chem Commun (1988) 53:2753-2777; Rosenberg,et al, Coll Czech Chem Commun (1988) 5212792-2800; Rosenberg, et al,Coll Czech Chem Commun (1988) 52:2801-2808; Starrett, et al, AntiviralRes (1992) 19:267-273; Yu, et al, J Med Chem (1992) 35:2958-2969;Wolff-Kugel, et al, Tet Lett (1991) 32:6341-6344.

A characteristic of nucleotide analogs or nucleotides having aphosphonate or a phosphate group is the presence of one or two negativecharges associated with the phosphorus group at physiologic pH. Thecharge associated with moieties such as phosphate or phosphonate groupsis believed to generally limit bioavailability by limiting cell membranepermeation via passive diffusion (Liebman, et al, J. Biol. Chem., (1955)216:823-830; Roll, et al, J Biol Chem, (1956) 220:439-444; Srivastava,et al, Bioorg Chem (1984) 12:118-129; Palu, et al, Antiviral Res (1991)16:115-119; Sastry, et al, Mol Pharmacol (1992) 41:441-445). Thesecompounds are often, therefore, given parentally in order to enhancebioavailability by increasing serum or intracellular levels.

Other characteristics of nucleotide analogs that can limit theirefficacy include unfavorable pharmacokinetic or pharmacodynamicproperties, insufficient potency and/or unfavorable toxicitycharacteristics.

Studies were conducted to ameliorate one or more of the above-mentionedproblems associated with nucleotide analog drugs. The present inventionincludes novel nucleotide analogs that are hydrolyzable in vivo. Thenucleotide analogs can have improved bioavailability, improvedpharmacokinetic or pharmacodynamic properties, enhanced potency and/orimproved toxicity characteristics compared to the correspondingunmodified nucleotide analog. Methods to synthesize and use thecompounds and methods to obtain and use antibodies that recognize thecompounds are also disclosed.

SUMMARY OF THE INVENTION

In a principal embodiment, the objects of this invention areaccomplished by a nucleotide analog amidate comprising a phosphonateradical wherein the improvement comprises an amino acid residue orpolypeptide radical in which an amino group of the amino acid orpolypeptide is bonded to the phosphorus atom of the nucleotide analog byan amidate bond, a carboxyl group of the amino acid residue orpolypeptide radical is positioned such that it is capable as the freeacid of hydrolyzing the phosphoroamidate bond, and the carboxyl group isblocked (such as by moieties including esters or amides). The nucleotideanalog amidates of this invention are hydrolyzed in vivo to thecorresponding nucleotide analog and are thus precursors of thecorresponding nucleotide analog.

In accordance with this invention the nucleotide analog amidates or aphysiologically acceptable salt thereof, have the structure of formula I

wherein L¹ and L² are independently an amino acid or polypeptide residuebonded to the phosphorus atom of the nucleotide analog by an amidatebond, or L¹ or L² are an oxyester, thioester, a substituted orunsubstituted amine, or hydroxy, provided that one or both of L¹ and L²is an amino acid or polypeptide residue and any carboxyl group that islinked by less than about 5 atoms to the amidate N is esterified oramidated, the dotted lines represent facultative bonds and wherein, (i)P and Z are linked to form a compound of the formula Ib

or (ii) L¹ and Z are linked to form a compound of the formula Ic

wherein

substituents linked to carbon atoms designated # are in the R, S or RSconfiguration;

X¹ is O or S;

Z is—CHR⁷—R¹¹—(CH₂)_(m1)—C#(R⁸)((CH₂)_(m2)(R⁹))—(CH₂)_(m3)—R¹⁰—(CH₂)_(m4)—,-Q-C₆H₄—CH₂—, —CHR⁷—O—CHR⁷—O—CHR⁷—, —CHR⁷—(CHR¹³)_(m1)—CHR¹⁴—R¹⁰—,

or VIIIwherein

R⁷ is H or C₁-C₄ alkyl;

R⁸ is H or C₁-C₄ alkyl, C₂-C₄ alkenyl, azidomethyl or azidoethyl;

R⁹ is halogen (F, Cl, Br or I), H or OH;

R¹⁰ is O, CH₂ or a chemical bond;

R¹¹ is O, S, CH₂, CHF or CF₂;

Q is —C(R¹²)₂—CH₂—, —C(R¹²)₂—O—, —CR¹²═CR¹²—, or —C≡C—, wherein each R¹²is independently H, or halogen;

R¹³ is H, halogen, OH, CH₃, CH₂OH, or C₃-C₆ acyloxymethyl;

R¹⁴ is H, halogen, OH, CH₃, CH₂OH, C₃-C₆ acyloxymethyl, or C₂-C₆acyloxy;

R²⁵ is CH₂, CHF or O;

R²⁶ is CH or S, provided that when R²⁵ is CH, R²⁶ is not S;

R²⁷ is H, OH, halogen, N₃, C₁-C₄ alkyl, C₁-C₄ alkoxy or, when R²⁶ is S,R²⁷ is absent;

R^(27a) is H, OH, halogen, N₃, C₁-C₄ alkyl, C₁-C₄ alkoxy;

R²⁸ is H, OH, halogen, N₃, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R²⁹ is O, S, CH₂, CHF, CF₂;

R³² is O;

m1 is an integer having a value from 0 to 4;

m2 is an integer having a value from 0 to 4;

m3 is an integer having a value from 0 to 4;

m4 is an integer having a value from 0 to 4;

B is a heterocyclic base; and

substituents linked to the carbon atom designated C# are in the R, S orRS configuration.

In a further embodiment the objects are accomplished by compounds of theformula II, IIa, IIb and IIc

wherein L² is OR, SR or

n is an integer having a value from 1 to 5 and if n>1, each —C(R³)(R²)—may be the same or different;

n1 is an integer;

substituents linked to the carbon atom designated # are in the R, S orRS configuration;

R is H, C₁-C₂₀ alkyl which is unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N and halogen (F, Cl, Br, I), C₃-C₂₀ aryl which is unsubstituted orsubstituted by substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl (1 to 3 halogenatoms), cyano, nitro, OH, O, N and halogen or R is C₄-C₂₀ aryl-alkylwhich is unsubstituted or substituted in the aryl moiety by substituentsindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, Nand halogen, or R is C₃-C₂₄ 1-acyloxy-1-alkyl (C₁-C₈ alkyl), or R isC₆-C₂₄ 1-acyloxy-1-aryl-1-alkyl (C₁-C₆ aryl, C₁-C₄ alkyl), or R isC₃-C₂₄ 1-acyloxy-2-alkoxy-1-alkyl (C₁-C₈ alkyl), or R is C₃-C₂₄1-acyloxy-2-haloalkyl (C₁-C₈ haloalkyl, 1 to 3 halogen atoms);

R¹ is H or C₁-C₉ alkyl, which is unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N, COOR⁴ and halogen, C₃-C₆ aryl which is unsubstituted or substitutedby substituents independently selected from the group consisting of OH,O, N, COOR⁴ and halogen or C₃-C₉ aryl-alkyl which is unsubstituted orsubstituted by substituents independently selected from the groupconsisting of OH, O, N, COOR⁴ and halogen;

R² is H or C₁-C₉ alkyl which is unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N, COOR⁴ and halogen, C₃-C₆ aryl which is unsubstituted or substitutedby substituents independently selected from the group consisting of OH,O, N, COOR⁴ and halogen or C₃-C₉ aryl-alkyl which is unsubstituted orsubstituted by substituents independently selected from the groupconsisting of OH, O, N, COOR⁴ and halogen;

R³ is C(O)—OR⁴, amino, amide, guanidinyl, imidazolyl, indolyl,sulfoxide, phosphoryl, C₁-C₃ alkylamino, C₁-C₃ alkyldiamino, C₁-C₆alkenylamuino, hydroxy, thiol, C₁-C₃ alkoxy, C₁-C₃ alkthiol,(CH₂)_(n)COOR⁴, C₁-C₆ alkyl which is unsubstituted or substituted withOH, halogen, SH, NH₂, phenyl, hydroxyphenyl or C₇-C₁₀ alkoxyphenyl;C₂-C₆ alkenyl which is unsubstituted or substituted with OH, halogen,SH, NH₂, phenyl, hydroxyphenyl or C₇-C₁₀ alkoxyphenyl; C₆-C₁₂ aryl whichis unsubstituted or substituted with OH, halogen, SH, NH₂, phenyl,hydroxyphenyl or C₇-C₁₀ alkoxyphenyl; and

R⁴ is H provided that nl greater than 1, or is C₃-C₉ alkyl which issubstituted by substituents independently selected from the groupconsisting of OH, O, N and halogen, C₃-C₆ aryl which is substituted bysubstituents independently selected from the group consisting of OH, O,N and halogen or C₃-C₉ aryl-alkyl which is substituted by substituentsindependently selected from the group consisting of OH, O, N andhalogen.

The structural formula I is meant to define compounds where thephosphorus (P) atom is tetravalent (PV oxidation state) and optionallylinked via the facultative bonds shown as dotted lines to either L¹ or Zto form a heterocyclic ring containing at least the P atom itself and anitrogen atom of L¹ or an atom present, usually oxygen (O), in Z. Forsuch compounds, L2 and the facultative bond between P and Z is absent.Such heterocyclic rings will preferably be 5-, 6- or 7-membered, but arealso 4-, 8-, 9-, 10-, 11- or 12-membered. Alternatively the P atom iscovalently linked to L² with L¹ and Z optionally linked to each other toform a heterocyclic ring. The structure is not intended to includecompounds where L¹, L² and a heterocyclic ring containing P and Z arepresent in the same molecule which would exceed the valency of P. Thus,an exemplary class of compounds is represented by the structure offormula I includes (L¹)(L²)P(O)—Z—B (formula Id) where no heterocyclicrings are formed between any L¹, L², P, Z or B moiety.

R² includes methyl, ethyl, propyl, isopropyl and benzyl.

In another embodiment, the objects of this invention are accomplished bya nucleotide analog ester comprising a phosphonate radical and an estermoiety bonded to the phosphorus atom of the nucleotide analog. Thenucleotide analog esters of this invention are hydrolyzed in Vivo to thecorresponding nucleotide analog and are thus precursors of thecorresponding nucleotide analog, or can be used as intermediates in thesynthesis of the nucleotide analog amidates.

The substructure Z can have a range of atoms between the base, B, andthe phosphorus atom. For example, four atoms separate the heterocyclicbase and phosphorus moieties when Z is of the formula —CH₂—O—CH₂—CH₂—.In general, there will be from 2 to 16 atoms, preferably from 3 to 9atoms, more preferably from 4 to 6 atoms that separate the heterocyclicbase and the phosphorus atom. Thus, Z substructures of the formula—CHR⁷—R¹¹—(CH₂)_(m1)—C(R⁸)((CH₂)_(m2)(R⁹))—(CH₂)_(m3)—R¹⁰—(CH₂)_(m4)—may be characterized where the sum of m1, m3 and m4 is in a rangebetween 0 and 12 or preferably in a range between 1 and 6, morepreferably in a range between 1 and 4.

The nucleotide analog amidate and ester compounds of the instantinvention include the corresponding salts, which may be base salts ofthe phosphonic acid moiety or an acid addition salt of the base inaddition to the zwitterionic forms and/or solvates of compounds offormula I.

Some of the compounds of the present invention can exist as opticalisomers and both racemic or scalemic and diastereomeric mixtures ofthese isomers which may exist for certain compounds as well as theindividual optical isomers which are all within the scope of the presentinvention. Compounds of formula IIa in the R, S or RS configuration atthe chiral carbon, designated # herein, are examples of compounds havingoptical isomers. While the scalemic mixtures can be separated into theirindividual isomers through well-known techniques such as, for example,the separation of diastereomeric salts formed with optically activeadjuncts, e.g. acids or bases followed by conversion back to theoptically active substrates; in most instances, for compounds of thepresent invention, the preferred optical isomer can be synthesized bymeans of stereospecific reactions, beginning with the appropriatestereoisomer of the desired starting material.

As indicated, the present invention also pertains to the salts,including pharmaceutically acceptable non-toxic salts of thesecompounds. Such salts may include those derived by combination ofappropriate cations such as alkali and alkaline earth metal ions orammonium and quaternary amino ions with the acid anion moiety of thephosphonic acid group. In addition salts may be formed from acidaddition of certain organic and inorganic acids with basic centers ofthe purine, specifically guanine, or pyrimidine base. Finally it is tobe understood that compounds of the present invention in theirun-ionized as well as zwitterionic form and/or in the form of solvatesare also considered part of the present invention.

In other embodiments, the foregoing nucleotide analog amidates andesters or their dihydroxy phosphonate hydrolysis products are labeledwith a detectable tag such as a radioisotope (including ³²P, ³⁵S, ¹⁴C,³H, ¹²⁵I), a fluorescent moiety, an enzyme (including peroxidase,phosphatase) or the like.

In other embodiments, the foregoing nucleotide analog amidates compriseamino acid, dipeptide or tripeptide compounds (monosubstituted ordisubstituted with identical or different amino acid, dipeptide ortripeptide substituents) that are capable of entry into eukaryotic cellsvia amino acid or peptide transporters present in eukaryotic cells invivo or in vitro.

Also included are immunogens for raising antibodies which are capable ofbinding to the nucleotide analog amidates and esters of this inventionand/or their dihydroxy phosphonate hydrolysis products, as well asantibodies capable of binding to the amidate and ester compounds of thisinvention or to their dihydroxy phosphonate hydrolysis products.

Chemical Structures

Structural formulas and substructures are represented as roman numerals(I, II, III, IV, V, etc) or as letters (B, Z, L¹, L², R¹, R², etc). Thesubstructures Z and Z¹ represent linking groups between the heterocyclicbase (B) and the phosphorus atom (P) of the phosphonate group in thenucleotide analogs described herein. Linking groups Z, such as—CHR⁷—R¹¹—(CH₂)_(m1)—C(R⁸)((CH₂)_(m2)(R⁹))—(CH₂)_(m3)—R¹⁰—(CH)_(m4)—, inthe structure (L¹)(L²)P(O)-Z-B have the structure(L¹)(L²)P(O)—CHR⁷—R¹¹—(CH₂)_(m1)—C(R⁸)((CH₂)_(m2)(R⁹))—(CH₂)_(m3)—R¹⁰—(CH₂)_(m4)—B(i.e. the heterocyclic base (B) is covalently linked to the unfilledvalence on the right side of the structure and the phosphorus atom islinked to the unfilled valence on the left side).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Synthesis of formula Ib compounds where X¹ is S.

FIG. 2. Synthesis of formula Ia compounds.

FIG. 3. Synthesis of formula IV compounds.

FIG. 4. Synthesis of formula VII compounds.

FIG. 5. Synthesis of formula VIII compounds.

FIG. 6. Synthesis of formula VI compounds.

FIG. 7. Synthesis of formula VI compounds.

DETAILED DESCRIPTION OF THE INVENTION

Amino Acid Residues. When groups L¹ or L² comprise an amino acid residuethey comprise any naturally-occurring or synthetic amino acid residue,i.e., any moiety comprising at least one carboxyl and at least one aminoresidue directly linked by at least one carbon atom, typically a single(α) carbon atom. The nature and identity of the intervening structurelocated between the carboxyl and amino (amidate) groups can have avariety of structures including those described herein. Al that isnecessary is that the group have sufficient conformation arid length tobe capable of acid catalysis of the phosphoroamidate bond and release ofthe phosphonate when the free carboxyl is generated in vivo, e.g. bydeesterification, deamidation or peptidolytic cleavage of the precursor.In general, the amino acids corresponding to the residues employed inthe compounds of this invention are naturally occurring and have nopharmacological activity per se. However, optimal pharmacokineticactivity (substantially complete autocatalytic hydrolysis uponhydrolysis of the distal amide or ester bond) may be achieved by usingnon-naturally occurring amino acid residues. The intervening structuremay be as simple as methylene (when the residue is glycyl) orsubstituted methylene (other a amino acids). The structure, ordinarilycontains up to about 5 carbon or hetero atoms in the direct linkagebetween the carboxyl carbon and the amidate nitrogen, as for example inthe case of intervening ethylene, propylene, butylene, or pentylenegroups or their substituted analogs, such as for example oxyesters inwhich O replaces carbon and, as appropriate, hydrogen. An example ofsuch an intervening structure would be —CH—O—CH(R³)(R²)—. In general,fewer intervening atoms are employed when more rapid hydrolysis isdesired, although it will be understood that larger structures aresuitable if they possess sufficient flexibility or have conformations inwhich the carboxyl group is positioned in proximity to the amidate bond.

In general, the amino acid residue has the structure shown in formulaIII. Ordinarily, n is 1 or 2, R² is H and R³ is a moiety containing oneor more of the following groups: amino, carboxyl, amide, carboxyl ester,hydroxyl, C₆-C₇ aryl, ether, n-, s- or t-alkyl (C₁-C₆), guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and phosphoryl. The R² andR³ substituents can have a wide variety of structures including thosedisclosed herein.

Ordinarily R² is H and R³ is a side chain or group of a naturallyoccurring amino acid. With respect to the carboxyl-containing sidechains it will be understood that if the C atom of the subject carboxylis linked by 5 or less atoms to the phosphoamide N then the carboxyloptionally will be blocked, e.g. by esterification or amidation whereinthe ester or amide bonds are hydrolyzable in vivo. R³ also is takentogether with R¹ to form a proline residue (R³═—CH₂—)₃) Thus, R³ isgenerally a side group such as H, —CH₃, —CH(CH₃)₂, —CH₂—CH(CH₃)₂,—CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH, —CH(OH)—CH₃—, —CH₂—SH,—CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂, —CH₂—COOH, —CH₂—CH₂—COOH,—(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R³ also includes1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,indol-3-yl, methoxyphenyl and ethoxyphenyl. The optimal R³ group isreadily selected using routine assays.

When the amino acid residues contain one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof, fall within the scope of this inventioit Ingeneral, if it is desired to rely on non-enzymatic means of hydrolysis,D isomers should be used. On the other hand, L isomers may be moreversatile since they can be susceptible to both non-enzymatic as well aspotential targeted enzymatic hydrolysis, and are more efficientlytransported by amino acid or dipeptidyl transport systems in thegastrointestinal tract.

Examples of suitable amino acid residues include the following:

Glycyl;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid residues;

Amino acid amides such as glutaminyl and asparaginyl;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, 5-hydroxy-2,6-diaminohexanoic acid (commonly,hydroxylysine, including allohydroxylysine) and diaminobutyric acidresidues;

Other basic amino acid residues such as histidinyl;

Diarninodicarboxylic acids such as α,α′-diaminosuccinic acid,α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid, α,α′-diaminopimelicacid, α,α′-diamino-β-hydroxypimelic acid, α,α′-diaminosuberic acid,α,α′-diaminoazelaic acid, and α,α′-diaminosebacic acid residues;

Imino acids such as proline, 4- or 3-hydroxy-2-pyrrolidinecarboxylicacid (commonly, hydroxyproline, including allohydroxyproline),γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid,—N([CH₂]_(n)COOR⁴)₂, wherein n and R⁴ are as defined above, andazetidine-2-carboxylic acid residues;

A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino acid suchas alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-aminoα-methyl-ε-hydroxycaptoic acid, isovaline, α-methylglutamnicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid; isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid residues; β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid residues;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,γ-hydroxynorvaline, δ-hydroxynorvaline and epsilon-hydroxynorleucineresidues; canavinyl and canalinyl; γ-hydroxyornithinyl;

2-hexosaminic acids such as D-glucosarminic acid or D-galactosaminicacid residues;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine residues;

Other sulfur containing amino acid residues including cysteine;homocystine; β-phenylmethionine; methionine; S-allyl-L-cysteinesulfoxide; 2-thiolhistidine; cystathionine; and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted a amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropioric acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-icloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro,2-hydroxy-5-nitro and p-nitro-phenylalanine); furyl-, thienyl-,pyridyl-, pyrimidinyl-, purine or naphthylalanines; and tryptophananalogues and derivatives including kynurenine, 3-hydroxykynurenine,-2-hydroxytryptophan and 4-carboxytryptophan residues;

α-Amino substituted amino acid residues including sarcosine(N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acid residues includingserine, thtelonine, allothreonine, phosphoserine and phosphothreonineresidues.

Any one of the foregoing or other known amino acids are suitablyemployed in this invention provided that they are capable ofautocatalytically hydrolyzing the amidate bond. Thus, they must contain,or must, upon being converted (hydrolyzed) in vivo, contain a freecarboxyl group. In general, the amino acids corresponding to theresidues employed in the compounds of this invention are naturallyoccurring and have no pharmacological activity. However, optimalpharmacokinetic activity may be achieved by the use of non-naturallyoccurring amino acid residues.

Of particular interest are hydrophobic residues such as mono- ordi-alkyl or aryl amino acids, cycloalkylamino acids and the like. Theseresidues, together with R⁴, contribute to cell permeability byincreasing the partition coefficient of the nucleotide analog amidate.Typically, the residue does not contain a sulfhydryl or guanidinosubstituent.

Polypeptide Radicals. If nil is greater than 1, then the group shown informula II, IIa, IIb or III is greater than 1, then the moiety comprisesa polypeptide radical. This comprises dipeptides, short polypeptides of3, 5 or 10 residues, or proteins having up to 100 or more residues. Forthe most part, dipeptides not containing aspartic or glutamic acid inthe residue adjacent to the P atom, will not autocatalytically hydrolyzethe amidate bond and therefore the carboxyl groups (generally 1 or 2) inthe distal residue do not need to be esterified or amidated, i.e., R⁴can be H in these circumstances. However, if such compounds are intendedto be used as precursors for the free phosphonate nucleotide analog invivo rather than as immunogens for example, the polypeptides ordinarilywill contain a peptidolytic enzyme cleavage site at the peptide bondlinking the first residue and the next residue distal to the phosphorusatom. Such cleavage sites are flanked by enzymatic recognitionstructures, e.g. particular residues recognized by a hydrolytic enzyme.

Peptidolytic enzymes are well known, and in particular includecarboxypeptidases. Carboxypeptidases digest polypeptides by removingC-terminal residues, and are specific in many instances for particularC-terminal sequences. Such enzymes and their substrate requirements ingeneral are well known. For example, a dipeptide having a given pair ofresidues and a free carboxyl terminus is covalently bonded through itsα-amino group to the phosphorus atom of the invention nucleotideanalogs. It is expected that this peptide will be cleaved by theappropriate dipeptidase or protease, leaving the carboxyl of theproximal amino acid residue to autocatalytically cleave the amidatebond.

Examples of suitable dipeptidyl groups (designated by their singleletter code) include AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM,AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL,RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ NG, NH,NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ,DG, DH, DL, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC,CE, CQ, CG, CH, CI, CL, CK, CM,CF, CP, CS, CT, CW, CY, CV, EA, ER, EN,ED, EC, EE, EQ EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA,QR, QN, QD, QC, QE, QQ QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY,QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT,GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP,HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ IG, IH, II, IL, IK, IM,IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL,LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH,KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ,MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC,FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN,PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA,SR, SN, SD, SC, SE, SQ, SG, SH, SI, St, SK, SM, SF, SP, SS, ST, SW, SY,SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT,TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP,WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM,YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL,VK, VM, VF, VP, VS, VT, VW, VY and VV.

Exemplary dipeptidyl compounds have the structure of formula IX whereinR² is H, R³ is the side chain of a naturally occurring amino acid, L¹,R⁴, B and Z are as defined above.

Tripeptides are also useful. The sequence -X4-pro-X5-(where X4 is anyamino acid residue and X5 is an amino acid residue, a carboxyl ester ofproline or hydrogen) will be cleaved by luminal carboxypeptidase toyield X4 with a free carboxyl, which inb turn autocatalytically cleavesthe phosphono amidate bond. X5 usually will be a benzyl ester of thecarboxy group of X5. Thus, n1 is usually 1, 2 or 3, but may range up to5, 10, 100 or more residues.

If the amino acid residue has 2 or more amine groups, e.g., a lysinyl orarginyl, or ornithinyl residue, then R³ represents the group—[C(R⁶)₂]_(n2)N(R²)— where n2 is 0 to 6, R⁶ is H, C₁-C₂₀ alkyl, C₆-C₂₀aryl, C₇-C₂₀ alkylaryl, C₇-C₂₀ arylalkyl, C₁-C₂₀ alkoxy, C₆-C₂₀ aryloxyor hydroxyl, and R² is defined above. Such compounds will contain aplurality of phosphonate moieties. For example when both the epsilon(ε)/delta (δ) and alpha (α) amino groups of lysine or ornithine aresubstituted with nucleotide phosphonate moieties the amidate is believedto be capable of releasing two molecules of active drug, each expectedto emerge under different pharmacokinetics and therefore furthersustaining the drug release.

The number of amino acid residues, n1, in the nucleotide analog amidatesof this invention can vary extensively. Where n1=1, a single ariino acidis found at the designated site, and where n1>1 then a polypeptideradical is present. Typically, n1 is 1 or 2, but may range up to 3, 5,10 or 100 or more residues.

If the residue is immediately adjacent to the phosphonate atom and itsside chain contains a carboxyl group, e.g. in the case of glutamic acidor aspartic acid, then this carboxylate is substituted with R⁴.

The amidate group optionally is taken together with Z to form a cyclicamidate precursor. Such compounds have structure XIV.

wherein L², R¹, R², R³, Z, n1 and B are as defined above. Typically, inthis embodiment R³ is not carboxyl, R² is H, and n1 is 1.

Hydrolysis of the cyclic amidates of formulas IIa-c and IV leaves ahydroxyl-substituted substructure Z and the free carboxyl, which in turnwill autolyze the amidate. Substructures Z in which the methylenebackbone is substituted with hydroxymethyl are advantageous in thisembodiment, particularly linkers in compounds of the formula—CH₂OCH(CH₂O—)CH₂—B.

Heterocyclic bases. The compounds of this invention comprise anynaturally-occurring heterocycle found in nucleic acids, nudeotides ornucleosides, or analogs thereof. The radicals of such heterocyclicbases, designated herein as B, are generally the purine, pyrirnidine orrelated heterocycles shown in formulas X-XIII.

wherein R¹⁵ is H, OH, F, Cl, Br, I, OR¹⁶, SH, SR¹⁶, NH₂, or NHR¹⁷;

R¹⁶ is C₁-C₆ alkyl including CH₃, CH₂CH₃, CH₂CCH (2-propynyl), CH₂CHCH₂(2-allyl), C₃H₇;

R¹⁷ is C₁-C₆ alkyl including CH₃, CH₂CH₃, CH₂CCH, CH₂CHCH₂, C₃H₇;

R¹⁸ is N, CF, CCl, CBr, CI, CR¹⁹ or CSR¹⁹, COR¹⁹;

R¹⁹ is H, C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl or C₇-C₉ arylalkylunsubstituted or substituted by OH, O, N, F, Cl, Br or I including CH₃,CH₂CH₃, CHCH₂, CHCHBr, CH₂CH₂Cl, CH₂CH₂F, CH₂CCH, CH₂CHCH₂, C₃H₇, CH₂OH,CH₂OCH₃, CH₂OC₂H₅, CH₂OCCH, CH₂OCH₂CHCH₂, CH₂C₃H₇, CH₂CH₂OH, CH₂CH₂OCH₃,CH₂CH₂OC₂H₅, CH₂CH₂OCCH, CH₂CH₂OCH₂CHCH₂, CH₂CH₂OC₃H₇;

R²⁰ is N or CH;

R²¹ is N, CH, CCN, CCF₃, CC≡CH or CC(O)NH₂;

R²² is H, OH, NH₂, SH, SCH₃, SCH₂CH₃, SCH₂CCH, SCH₂CHCH₂, SC₃H₇,NH(CH₃), N(CH₃)₂, NH(CH₂CH₃), N(CH₂CH₃)₂, NH(CH₂CCH), NH(CH₂CHCH₂),NH(C₃H₇) or halogen (F, Cl, Br or I);

R²³ is H, OH, F, Cl, Br, I, SCH₃, SCH₂CH₃, SCH₂CCH, SCH₂CHCH₂, SC₃H₇,OR¹⁶, NH₂, or NHR¹⁷; and

R²⁴ is O, S or Se.

B includes both protected and unprotected forms of the heterocyclicbases. Protecting groups for exocyclic amines and other groups are known(Greene and include N-benzoyl, isobutyryl, 4,4′-dirnethoxytrityl (DMT)and the like. The selection of a protecting group will be apparent tothe ordinary artisan and will depend on the nature of the labile groupand the chemistry which the protecting group is expected to encounter,e.g., acidic, basic, oxidative, reductive or other conditions.

As used herein, B¹ is a protected heterocyclic base having the formulaXa, XIa, XIb, XIIa or XIIIa

wherein R¹⁸, R²⁰, R²¹, R²⁴ have the meanings previously defined; R^(22A)is R³⁹ or R²² provided that R²² is not NH₂; R^(23A) is R³⁹ or R²³provided that R²³ is not NH₂; R³⁹ is NHR⁴⁰, NHC(O)R³⁶ or NCR⁴¹N(R³⁸)₂wherein R³⁶ is C₁-C₁₉ alkyl, C₁-C₁₉ alkenyl, C₃-C₁₀ aryl, adamantoyl,alkylanyl, or C₃-C₁₀ aryl unsubstituted or substituted with 1 or 2 atomsor groups selected from halogen, methyl, ethyl, methoxy, ethoxy, hydroxyand cyano; R³⁸ is C₁-C₁₀ alkyl, or both R³⁸ together are 1-morpholino,1-piperidine or 1-pyrrolidine; and R⁴¹ is hydrogen or CH₃. Forheterocyclic bases of structures XIa and XIb, if R³⁹ is present atR^(22A) or R^(23A), both R³⁹ groups on the same heterocyclic base willgenerally be the same. Exemplary R⁴⁰ include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, decanyl,lauryl and hexadecyl).

Specific heterocyclic bases include hypoxanthine, inosiine, thymine,uracil, xanthine, 8-aza derivatives of 2-aminopurine, 2,6-diaminopurine,2-amino-6-chloropurine, hypoxanthine, inosine and xanthine;7-deaza-8-aza derivatives of adenine, guanine, 2-aminopurine,2,6-diaminopurine, 2-amino-6-chloropurine, hypoxanthine, inosine andxanthine; 1-deaza derivatives of 2-aminopurine, 2,6-diaminopurine,2-amino-6-chloropurine, hypoxanthine, inosine and xanthine; 7-deazaderivatives of 2-aminopurine, 2,6-diaminopurine, 2-amino-6-chloropurine,hypoxanthine, inosine and xanthine; 3-deaza derivatives of2-aminopurine, 2,6-diaminopurine, 2-amino6-chloropurine, hypoxanthine,inosine and xanthine; 6-azacytosine; 5-fluorocytosine; 5-chlorocytosine;5-iodocytosine; 5-bromocytosine; 5-methylcytosine; 5-bromovinyluracil;5-fluorouracil; 5-chlorouracil; 5-iodouracil; 5-bromouracil;5-trifluoromethyluracil; 5-methoxymethyluracil; 5-ethynyluracil;5-propynyluracil and the like.

Preferably, B is a 9-purinyl residue selected from guanyl,3-deazaguanyl, 1-deazaguanyl, 8-azaguanyl, 7-deazaguanyl, adenyl,3-deazaadenyl, 1-dezazadenyl, 8-azaadenyl, 7-deazaadenyl,2,6-diaminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl and6-thio-2-aminopurinyl, or a, B is a 1-pyrimidinyl residue selected fromcytosinyl, 5-halocytosinyl, and 5-(C₁-C₃-alkyl)cytosinyl.

The invention compounds, such as those of the formulas (L¹)(RO)P(O)-Z-B,are optionally esterified at the phosphorus atom by the group R definedabove. Exemplary R groups include, phenyl, 2- and 3-pyrrolyl, 2- and3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and4-pyrazolyl, 2-, 3- and 4-pyridinyl, 2-, 4- and 5-pyrimidinyl, 2-, 3-and 4-alkoxyphenyl (C₁-C₁₂ alkyl including 2-, 3- and 4-methoxyphenyland 2-, 3- and 4-ethoxyphenyl), 2-, 3- and 4-halophenyl (including 2-,3- and 4-fluorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dihalophenyl (including 2,4-difluorophenyl and 2,4-dichlorophenyl),2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, C₁-C₁₂ alkylincluding 2-, 3- and 4-trifluoromethylphenyl and 2-, 3- and4-trichloromethylphenyl), 2-, 3- and 4-cyanophenyl, carboalkoxyphenyl(C₁-C₄ alkyl incl-uding 2-, 3- and 4-carboethoxyphenyl(—C₆H₄—C(O)—OC₂H₅) and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dicarboethoxyphenyl), 1-, 2-, 3-, and 4-pyridinyl (—C₅H₄N), 2-, 3-and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms,C₁-C₂ alkyl including 4-trifluoromethylbenzyl), alkylsalicylphenyl(C₁-C₄ alkyl including 2-, 3- and 4ethylsalicylpheryl), 2-,3- and4-acetylphenyl, 1,8-dihydroxynaphthyl (—O—C₁₀H₆—OH or —O—C₁₀H₆—O—),2,2′-dihydroxybiphenyl (—O—C₆H₄—C₆H₄—O—; both oxygen atoms are linked tothe phosphorus atom), alkoxy ethyl [C₁-C₆ alkyl including —CH₂—CH₂—O—CH₃(methoxy ethyl) and phenoxymethyl], aryloxy ethyl [C₆-C₉ aryl (includingphenoxy ethyl) or C₆-C₉ aryl substituted by OH, NH₂, halo, C₁-C₄ alkylor C₁-C₄ alkyl substituted by OH or by 1 to 3 halo atoms],—C₆H₄—CH₂—N(CH₃)₂, N-ethylmorpholino

O-(CH₂)₂—N[(CH₂)₂(CH₂)₂]O), adamantoyl oxymethyl,pivaloyloxy(methoxyethyl)methyl (—CH(CH₂CH₂OCH₃)—O—C(O)—C(CH₃)₃),

—O—CH₂—O—C(O)—C₁₀H₁₅), pivaloyloxymethyl (—CH₂—O—C(O)—C(CH₃)₃),pivaloyloxy(methoxymethyl)methyl (—CH(CH₂OCH₃)—O—C(O)—C(CH₃)₃),pivaloyloxyisobutyl (—CH(CH(CH₃)₂)—O—C(O)—C(CH₃)₃) isobutyryloxymethyl(—CH₂—O—C(O)—CH₂—CH(CH₃)₂), cyclohexanoyl oxymethyl (—CH₂—O—C(O)—C₆H₁₁),phenyl (—C₆H₅), benzyl (—CH₂—C₆H₅), isopropyl (—CH(CH₃)₂), t-butyl(—C(CH₃)₃), —CH₂—CH₃, —(CH₂)₂—CH₃, —(CH₂)₃—CH₃, —(CH₂)₄—CH₃,—(CH₂)₅—CH₃, —CH₂—CH₂F, —CH₂—CH₂Cl, —CH₂—CF₃, —CH₂—CCl₃, R⁵, NHR^(6A) orN(R^(6A))₂ wherein R⁵ is CH₂C(O)N(R^(6A))₂, CH₂C(O)OR^(6A),CH₂OC(O)R^(6A), CH(R^(6A))OC(O)R^(6A), CH₂C(R^(6A))₂CH₂OH, CH₂OR^(6A),NH—CH₂—C(O)O—CH₂CH₃, N(CH₃)—CH₂—C(O)O—CH₂CH₃, NHR⁴⁰, CH₂—O—C(O)—C₆H₅,CH₂—O—C(O)—C₁₀H₁₅, —CH₂—O—C(O)—CH₂CH₃, CH₂—O—C(O)—CH(CH₃)₂,CH₂—O—C(O)—C(CH₃)₃, CH₂—O—C(O)—CH₂—C₆H₅, wherein R^(6A) is C₁-C₂₀ alkylwhich is unsubstituted or substituted by substituents independentlyselected from the group consisting of OH, O, N and halogen (1 to 5halogen atoms), C₆-C₂₀ aryl which is unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N and halogen (1 to 5 halogen atoms) or C₇-C₂₀ aryl-alkyl which isunsubstituted or substituted by substituents independently selected fromthe group consisting of OH, O, N and halogen (1 to 5 halogen atoms),provided that for compounds of formulas N(R^(6A))₂, CH₂C(O)N(R^(6A))₂,CH₂C(O)OR^(6A), CH₂OC(O)R^(6A), CH(R^(6A))OC(O)R^(6A) andCH₂C(R^(6A))₂CH₂OH, the total number of carbon atoms present is lessthan 25 (preferably the number of carbon atoms present is about 4 toabout 14) and R⁴⁰ is C₁-C₂₀ alkyl.

The invention compounds are optionally alkylated at the α-nitrogen atomof the amino acid by the R¹ group defined above. Exemplary R¹ groupsinclude H, CH₃, CH₂CH₃, benzyl, 4-O-N-methylpiperidinyl

—O—CH[(CH₂)₂(CH₂)₂]N(CH₃)), 3-O—N-methylpiperidinyl and the like.

The invention compounds are optionally esterified at the amino acidcarboxyl moiety by the R⁴ group defined above. Exemplary R⁴ groupsinclude H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl (C(CH₃)₃),phenyl (—C₆H₅), benzyl (—CH₂—C₆H5), 1-pyridyl, 3-pyridyl, 1-pyrimidinyl,N-ethylmorpholino (—CH₂—CH₂—N[(CH₂)₂(CH₂)₂]O), N-2-propylmorpholino(—CH(CH₃)—CH₂—N[(CH₂)₂(CH₂)₂]O), methoxyethyl (—CH₂—CH₂—O—CH₃),4-N-methylpiperidyl (—CH[(CH₂)₂(CH₂)₂]N(CH₃)), 3-N-methylpiperidyl,phenol which is 2-, 3-, or 4-substituted by N(R³⁰)₂ where R³⁰ isindependently H or C₁-C₆ alkyl unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N, COOR⁴ and halogen or C₆-C₁₂ aryl unsubstituted or substituted bysubstituents independently selected from the group consisting of OH, O,N, COOR⁴, N(R⁷)₂ and halogen (including 2-, 3-, and4-N,N-dimethylaminophenol and 2-, 3-, and 4-N,N-diethylaminophenol),1-ethylpiperazinyl

—CH₂—CH₂—NC₄H₈NH], and N⁴-substituted 1-ethylpiperazinyl(—(CH₂)₂—N[(CH₂)₂(CH₂)₂]NR², where R² is as defined above).

Additional compounds that are included in the invention are nucleotideanalog dimers that are linked via an amino or carboxyl group. As usedherein, dimers (or trimers) refer to the presence of two (or three)nucleoside residues that comprise a compound. Thus, a -L¹-P(O)(L¹)-Z-Bor —P(O)(L¹)-Z-B radical covalently linked to a -L¹-P(O)(L¹)-Z-B or—P(O)(L¹)-Z-B radical gives B-Z-P(O)(L¹)-P(O)(L¹)-Z-B,B-Z-P(O)(L¹)-L¹-P(O)(L¹)-Z-B or B-Z-P(O)(L¹)-L¹-L¹-P(O)(L¹)-Z-B.

Dimer nucleotide analogs are conveniently linked via amino acids,diamino acids, dicarboxylic amino acids, diamines or dicarboxylic acidssuch as β-aminoalanine, diaminobutyric acid, citrulline, homoarginine,homocitrulline, ornithine, γ-aminobutyric acid, arginine, histidine,asparagine, glutamine, β-hydroxyaspartic acid, β-hydroxyglutamic acid,β-methylaspartic acid, β-methylglutamic acid, 3-aminoadipic acid,2-aminopimelic acid, 2-aminosuberic add, β-amino acid analogs of lysine(NH₂—(CH₂)₃—CH(NH₂)—CH₂—CH—C(O)OH), arginine, histidine, asparagine,glutamine and the like. Exemplary compounds include dimers linked vialysine or β-lysine having the formulasB-Z-P-(O)(L)-NH—(CH₂)₄—CH(C(O)OR⁴)—NR¹—P(O)(L)-Z-B andB-Z-P(O)(L)-NH—(CH₂)₃—CH(CH₂C(O)OR⁴)—NR¹—P(O)(L)-Z-B and dimers linkedvia aspartic or glutamic acid having the formulaB-Z-P(O)(L)-O—C(O)—(CH₂)₁₋₂—CH(C(O)OR⁴)—NR¹—P(O)(L)-Z-B. L, Z and B areindependently selected.

Nucleotide analogs comprising dipeptidyl or tripeptidyl L groups arealso included in the compounds of the invention. Nucleotide radicals arelinked through side chain groups (usually amino or carboxyl) or throughamino and carboxyl groups of the amino acids. Exemplary dipeptidyl andtripeptidyl dimers and trimers include compounds of the formulasB-Z-P(O)(L¹)-O—C(O)—(CR²R³)_(n)—NR¹—C(O)—(CR²R³)_(n)—NR¹—P(O)(L¹)-Z-B,B-Z-P(O)(L¹)-O—C(O)—(CR²R³)_(n)—NR¹—C(O)—(CR²R³)_(n)—NR¹—O—C(O)—(CR²R³)_(n)—NR¹—P(O)(L¹)-Z-B,B-Z-P(O)(L¹)—O—C(O)CR²(R³—P(O)(L¹)-Z-B)-NR¹—C(O)—(CR²R³)_(n)—NR¹—P(O)(L¹)-Z-BandB-Z-P(O)(L¹)-O—C(O)—(CR²R³)_(n)—NR¹—C(O)—CR²(R³—P(O)(L¹)-Z-B)-NR¹—P(O)(L¹)-Z-B.In order to provide a compound with a desired molar ratio of one Z-Bcompared to a second -Z-B, tetramer, pentamer and higher polymer formscan also be prepared where Z and/or B are independently chosen.

As used herein, and unless mocdiffed by the immediate context: 1) theterm alkyl, alkenyl and alkynyl refer to straight chain, branched andcyclic residues. Thus, C₁-C₄ alkyl includes methyl, ethyl, propyl,cyclopropyl, isopropyl, n-, sec-, iso- and tert-butyl, cyclobutyl andthe like while alkenyl includes ethenyl, propenyl, isopropenyl, 1-, 2-and 3-butenyl, 1- and 2-isobutenyl and the like. The term alkyl alsoincludes cyclic N-, S- or O-heterocarbonyl (such as piperidyl andmorpholino). 2) The term aryl includes N-, S- or O-heteroaryl, includingphenyl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and5-isothiazolyl, 3- and 4-pyrazolyl, 2-, 3- and 4-pyridinyl, 2-, 4- and5-pyrimidinyl. When “O” or “N” are substituted into aryl or alkyl thismeans that a ring or chain methyne or methylene is replaced by O, N orNH as the case may be. The term acyl means R^(X)—C(O)—, acyloxy meansR^(X)—C(O)—O—, acyloxymethyl means R^(X)—C(O)—O—CH₂— and thus, forexample, C₃₋₆ acyloxymethyl means R^(X)—C(O)—O—CH₂— wherein R^(X) is a 1to 4 carbon aikyl or aryl group (substituted or unsubstituted).

Nucleoside Phosphonates. Table 1 lists a group of exemplary nucleotideanalogs of formula I having the structure (L¹)(L²)P(O)-Z-B. Thesecompounds generally have L¹ and L² groups that, when amino acids, areidentical, although one of the amino acid groups can be different orreplaced by another hydrolyzable group such as —O—CH₂—O—(O)C(CH₃)₃ or—O—C₆H₅ as listed below.

TABLE 1 L¹, L²*  1 —NH—CH₂—C(O)—OR⁴  2 —NH—CH(CH₃)—C(O)—OR⁴  3—NH—CH(CH₃)₂—C(O)—OR⁴  4 —NH—CH(CH(CH₃)₂)—C(O)—OR⁴  5—NH—CH(CH₃)(CH₃)₂—C(O)—OR⁴  6 —NH—CH₂—CH₂—CH₂—CH—C(O)—OR⁴  7—NH—CH(CH₂—C₆H₅)—C(O)—OR⁴  8 —NH—CH(CH₂—C₈NH₆)—C(O)—OR⁴  9—NH—CH(CH₂—CH₂—S—CH₃)—C(O)—OR⁴ 10 —NH—CH(CH₂OH)—C(O)—OR⁴ 11—NH—CH(CH(OH)(CH₃)—C(O)—OR⁴ 12 —NH—CH(—CH₂SH)—C(O)—OR⁴ 13—NH—CH(CH₂—C₆H₅OH)—C(O)—OR⁴ 14 —NH—CH(CH₂—C(O)—NH₂)—C(O)—OR⁴ 15—NH—CH(CH₂—CH₂—C(O)—NH₂)—C(O)—OR⁴ 16 —NH—CH(CH₂C(O)OR⁴)—C(O)—OR⁴ 17—NH—CH(CH₂CH₂C(O)OR⁴)—C(O)—OR⁴ 18 —NH—CH(CH₂CH₂CH₂CH₂NH₂)—C(O)—OR⁴ 19—NH—CH(CH₂CH₂CH₂NHC(NH)(NH₂))—C(O)—OR⁴ 20 —NH—CH(CH₂C₃N₂H₃)—C(O)—OR⁴ 21—NH—CH(CH₃)₂—CH₂—C(O)—OR⁴ 22 —NH—CH₂—CH₂—C(O)—OR⁴ 23—NH—CH(CH₂—C₆H₅)—CH₂—C(O)—OR⁴ 24 —NH—CH(CH₂CH₂CH₂NH₂)—CH₂—C(O)—OR⁴ 25—NH—CH(CH₂CH₂CH₂CH₂NH₂)—CH₂—C(O)—OR⁴ 26—NH—CH(CH₂CH₂NHC(NH)(NH₂))—CH₂—C(O)—OR⁴ 27 —NH—CH(C(O)OR⁴)—CH₂—C(O)—OR⁴28 —NH—CH(CH₂C(O)OR⁴)—CH₂—C(O)—OR⁴ 29 —NH—CH(CH₂CH₂C(O)OR⁴)—CH₂—C(O)—OR⁴30 —N(CH₃)—CH₂—C(O)—OR⁴ 31 —NHR⁶ 32 —O—CH₂—CH₂—N[CH₂)₂(CH₂)₂]O 33—O—CH₂—O—C(O)—C(CH₃)₃ 34 —O—CH₂—O—C(O)—CH(CH₃)₂ 35—O—CH₂—O—C(O)—CH₂C₆H₄—O—CH₂CH₃ 36 —O—CH₂—O—C(O)—C_(1O)H₁₅ 37 —O—CH₂—C₆H₅38 —O—C₆H₅ 39 —O—CH₂—C₆H₄N(CH₃)₂ 40 —OH B  1 adenin-9-yl  2 guanin-9-yl 3 cytosin-1-yl  4 2, 6-diaminopurin-9-yl  5 2-aminopurin-9-yl  66-azacytosin-1-yl  7 1-deazaadenin-9-yl  8 3-deazaadenin-9-yl  98-azaadenin-9-yl 10 7-deaza-8-azaadenin-9-yl -Z-B**  1 —CH₂—O—CH₂—CH₂—B 2 —CH₂—O—C^(#)H(CH₂—OR⁴)—CH₂—B  3 —CH₂—O—C^(#)H(CH₃)—CH₂—B  4—CH₂—O—C^(#)H(CH₂F)—CH₂—B  5 —CH₂—O—C^(#)H(CH═CH₂)—CH₂—B  6—CH₂—O—C#H(CH₂N₃)—CH₂—B  7 ***  8 **** *R⁴ includes H, propyl,isopropyl, t-butyl, phenyl, benzyl, 1-pyridinyl, 1-pyrimidinyl,N-ethylmorpholino, methoxyethyl, 4-hydroxy-N-methylpiperidinyl,3-hydroxy-N-methylpiperidinyl, 1-ethylpiperazinyl; atoms with unfilledvalences are linked to each other. **The carbon atom on the left of eachstructure is attached to the phosphorus atom; ^(#)carbon atom havinglinked substituents in the R, S or RS configuration. *** - Z-Bsubstructure 7 is of formula V where R²⁵ and R²⁹ are O and B isthymin-1-yl (base 11) or one of the heterocyclic bases listed (1–10).**** - Z-B substructure 8 is of formula IV where R²⁵ and R²⁹ are O, R²⁶is S, R²⁷ is absent, R²⁸ is H and B is thymin-1-yl (base 11) or one ofthe heterocyclic bases listed (1–10) and includes the (+) and (−)enantiomers.

Compounds listed in Table 1 are designated herein by numbers assigned toL¹, L², Z and B according to the following convention, L¹.L².Z.B. Thus,compound 1.2.1.1, where R⁴ is benzyl, represents L¹ structure 1(—NH—CH₂—C(O)—O—CH₂—C₆H₅), L² structure 2 (—NH—CH(CH₃)—C(O)—O—CH₂—C₆H₅),Z structure 1 (—CH₂—O—CH₂—CH₂—) and B structure 1 (adenin-9-yl). Thiscompound would have the structure

which corresponds to the compound designated herein bis(alanyl benzylester)PMEA. Similarly, for the compound 7.7.1.1, L¹ structure 7(NH—H(CH₂—C₆H₅)—C(O)—OR⁴), L² structure 7 (NH—CH(CH₂—C₆H₅)—C(O)—OR⁴), Zstructure 2 (—CH₂—O—CH₂—CH₂—) and B structure 1 (adenin-9-yl) wouldhave, when R⁴ is methyl, the structure

and would represent the compound designated herein bis(phenylalanylmethyl ester)PMEA. Exemplary compounds include 1.1.1.1, 2.1.1.1,3.1.1.1, 4.1.1.1, 5.1.1.1, 6.1.1.1, 7.1.1.1, 8.1.1.1, 9.1.1.11,10.1.1.1, 11.1.1.1, 12.1.1.1, 13.1.1.1, 14.1.1.1, 15.1.1.1, 16.1.1.1,17.1.1.1, 18.1.1.1, 19.1.1.1, 20.1.1.1, 21.1.1.1, 22.1.1.1, 23.1.1.1,24.1.1.1, 25.1.1.1, 26.1.1.1,27.1.1.1, 28.1.1.1, 29.1.1.1, 30.1.1.1,31.1.1.1, 32.1.1.1, 33.1.1.1, 34.1.1.1, 35.1.1.1, 36.1.1.1, 37.1.1.1,38.1.1.1, 39.1.1.1, 40.1.1.1, 1.2.1.1, 2.2.1.1, 3.2.1.1, 4.2.1.1,5.2.1.1, 6.2.1.1, 7.2.1.1, 8.2.1.1, 9.2.1.1, 10.2.1.1, 11.2.1.1,12.2.1.1, 13.2.1.1, 14.2.1.1, 15.2.1.1, 16.2.1.1, 17.2.1.1, 18.2.1.1,19.2.1.1, 20.2.1.1, 21.2.1.1, 22.2.1.1, 23.2.1.1, 24.2.1.1, 25.2.1.1,26.2.1.1, 27.2.1.1, 28.2.1.1, 29.2.1.1,30.2.1.1, 31.2.1.1, 32.2.1.1,33.2.1.1, 34.2.1.1, 35.2.1.1, 36.2.1.1, 37.2.1.1, 38.2.1.1,39.2.1.1,40.2.1.1, 1.3.1.1, 2.3.1.1, 3.3.1.1, 4.3.1.1, 5.3.1.1, 6.3.1.1, 7.3.1.1,8.3.1.1, 9.3.1.1, 10.3.1.1, 11.3.1.1, 12.3.1.1, 13.3.1.1, 14.3.1.1,15.3.1.1, 16.3.1.1, 17.3.1.1, 18.3.1.1, 19.3.1.1, 20.3.1.1, 21.3.1.1,22.3.1.1, 23.3.1.1, 24.3.1.1, 25.3.1.1, 26.3.1.1, 27.3.1.1, 28.3.1.1,29.3.1.1, 30.3.1.1, 31.3.1.1, 32.3.1.1, 33.3.1.1, 34.3.1.1, 35.3.1.1,36.3.1.1, 37.3.1.1, 38.3.1.1, 39.3.1.1, 40.3.1.1, 1.4.1.1, 2.4.1.1,3.4.1.1, 4.4.1.1, 5.4.1.1, 6.4.1.1, 7.4.1.1, 8.4.1.1, 9.4.1.1, 10.4.1.1,11.4.1.1, 12.4.1.1, 13.4.1.1, 14.4.1.1, 15.4.1.1, 16.4.1.1, 17.4.1.1,18.4.1.1, 19.4.1.1, 20.4.1.1, 21.4.1.1, 22.4.1.1, 23.4.1.1, 24.4.1.1,25.4.1.1, 26.4.1.1, 27.4.1.1, 28.4.1.1, 29.4.1.1, 30.4.1.1, 31.4.1.1,32.4.1.1, 33.4.1.1, 34.4.1.1, 35.4.1.1, 36.4.1.1, 37.4.1.1, 38.4.1.1,39.4.1.1, 40.4.1.1, 1.5.1.1, 2.5.1.1, 3.5.1.1, 4.5.1.1, 5.5.1.1,6.5.1.1, 7.5.1.1, 8.5.1.1, 9.5.1.1, 10.5.1.1, 11.5.1.1, 12.5.1.1,13.5.1.1, 14.5.1.1, 15.5.1.1, 16.5.1.1, 17.5.1.1, 18.5.1.1, 19.5.1.1,20.5.1.1, 21.5.1.1, 22.5.1.1, 23.5.1.1, 24.5.1.1, 25.5.1.1, 26.5.1.1,27.5.1.1, 28.5.1.1, 29.5.1.1, 30.5.1.1, 31.5.1.1, 32.5.1.1, 33.5.1.1,34.5.1.1, 35.5.1.1, 36.5.1.1, 37.5.1.1, 38.5.1.1, 39.5.1.1, 40.5.1.1,1.6.1.1, 2.6.1.1, 3.6.1.1, 4.6.1.1,5.6.1.1, 6.6.1.1, 7.6.1.1, 8.6.1.1,9.6.1.1, 10.6.1.1, 11.6.1.1, 12.6.1.1, 13.6.1.1, 14.6.1.1, 15.6.1.1,16.6.1.1, 17.6.1.1, 18.6.1.1, 19.6.1.1, 20.6.1.1, 21.6.1.1, 22.6.1.1,23.6.1.1, 24.6.1.1, 25.6.1.1, 26.6.1.1, 27.6.1.1, 28.6.1.1, 29.6.1.1,30.6.1.1, 31.6.1.1, 32.6.1.1, 33.6.1.1, 34.6.1.1, 35.6.1.1, 36.6.1.1,37.6.1.1, 38.6.1.1, 39.6.1.1, 40.6.1.1, 1.7.1.1, 2.7.1.1, 3.7.1.1,4.7.1.1, 5.7.1.1, 6.7.1.1, 7.7.1.1, 8.7.1.1, 9.7.1.1, 10.7.1.1,11.7.1.1, 12.7.1.1, 13.7.1.1, 14.7.1.1, 15.7.1.1, 16.7.1.1, 17.7.1.1,8.7.1.1, 19.7.1.1, 20.7.1.1, 21.7.1., 22.7.1.1, 23.7.1.1, 24.7.1.1,25.7.1.1, 26.7.1.1, 27.7.1.1, 28.7.1.1, 29.7.1.1, 30.7.1.1, 31.7.1.1,32.7.1.1, 33.7.1.1, 34.7.1.1, 35.7.1.1, 36.7.1.1, 37.7.1.1, 38.7.1.1,39.7.1.1, 40.7.1.1, 1.8.1.1, 2.8.1.1, 3.8.1.1, 4.8.1.1, 5.8.1.1,6.8.1.1, 7.8.1.1, 8.8.1.1, 9.8.1.1, 10.8.1.1, 11.8.1.1, 12.8.1.1,13.8.1.1, 14.8.1.1, 15.8.1.1, 16.8.1.1, 17.8.1.1, 18.8.1.1, 19.8.1.1,20.8.1.1, 21.8.1.1, 22.8.1.1, 23.8.1.1, 24.8.1.1, 25.8.1.1, 26.8.1.1,27.8.1.1, 28.8.1.1, 29.8.1.1, 30.8.1.1, 31.8.1.1, 32.8.1.1, 33.8.1.1,34.8.1.1, 35.8.1.1, 36.8.1.1, 37.8.1.1, 38.8.1.1, 39.8.1.1, 40.8.1.1,1.9.1.1, 2.9.1.1, 3.9.1.1, 4.9.1.1, 5.9.1.1, 6.9.1.1, 7.9.1.1, 8.9.1.1,9.9.1.1, 10.9.1.1, 11.9.1.1, 12.9.1.1, 13.9.1.1, 14.9.1.1, 15.9.1.1,16.9.1.1, 17.9.1.1, 18.9.1.1, 19.9.1.1, 20.9.1.1, 21.9.1.1, 22.9.1.1,23.9.1.1, 24.9.1.1, 25.9.1.1, 26.9.1.1, 27.9.1.1, 28.9.1.1, 29.9.1.1,30.9.1.1, 31.9.1.1, 32.9.1.1, 33.9.1.1, 34.9.1.1, 35.9.1.1,36.9.1.1,37.9.1.1, 38.9.1.1, 39.9.1.1, 40.9.1.1, 1.10.1.1, 2.10.1.1, 3.10.1.1,4.10.1.1, 5.10.1.1, 6.10.1.1, 7.10.1.1, 8.10.1.1, 9.10.1.1, 10.10.1.1,11.10.1.1, 12.10.1.1, 13.10.1.1, 14.10.1.1, 15.10.1.1, 16.10.1.1,17.10.1.1, 18.10.1.1, 19.10.1.1, 20.10.1.1, 21.10.1.1, 22.10.1.1,23.10.1.1, 24.10.1.1, 25.10.1.1, 26.10.1.1, 27.10.1.1, 28.10.1.1,29.10.1.1, 30.10.1.1, 31.10.1.1, 32.10.1.1, 33.10.1.1, 34.10.1.1,35.10.1.1, 36.10.1.1, 37.10.1.1, 38.10.1.1, 39.10.1.1, 40.10.1.1,1.11.1.1, 2.11.1.1, 3.11.1.1, 4.11.1.1, 5.11.1.1, 6.11.1.1, 7.11.1.1,8.11.1.1, 9.11.1.1, 10.11.1.1, 11.11.1.1, 12.11.1.1, 13.11.1.1,14.11.1.1, 15.11.1.1, 16.11.1.1, 17.11.1.1, 18.11.1.1, 19.11.1.1,20.11.1.1, 21.11.1.1, 22.11.1.1, 23.11.1.1, 24.11.1.1, 25.11.1.1,26.11.1.1, 27.11.1.1, 28.11.1.1, 29.11.1.1, 30.11.1.1, 31.11.1.1,32.11.1.1, 33.11.1.1, 34.11.1.1, 35.11.1.1, 36.11.1.1, 37.11.1.1,38.11.1.1, 39.11.1.1, 40.11.1.1, 1.12.1.1, 2.12.1.1, 3.12.1.1, 4.12.1.1,5.12.1.1, 6.12.1.1, 7.12.1.1, 8.12.1.1, 9.12.1.1, 10.12.1.1, 11.12.1.1,12.12.1.1, 13.12.1.1, 14.12.1.1, 15.12.1.1, 16.12.1.1, 17.12.1.1,18.12.1.1, 19.12.1.1, 20.12.1.1, 21.12.1.1, 22.12.1.1, 23.12.1.1,24.12.1.1, 25.12.1.1, 26.12.1.1, 27.12.1.1, 28.12.1.1, 29.12.1.1,30.12.1.1, 31.12.1.1, 32.12.1.1, 33.12.1.1, 34.12.1.1, 35.12.1.1,36.12.1.1, 37.12.1.1, 38.12.1.1, 39.12.1.1, 40.12.1.1, 1.13.1.1,2.13.1.1, 3.13.1.1, 4.13.1.1, 5.13.1.1, 6.13.1.1, 7.13.1.1, 8.13.1.1,9.13.1.1, 10.13.1.1, 11.13.1.1, 12.13.1.4., 13.13.1.1, 14.13.1.1,15.13.1.1, 16.13.1.1, 17.13.1.1, 18.13.1.1, 19.13.1.1, 20.13.1.1,21.13.1.1, 22.13.1.1, 23.13.1.1, 24.13.1.1, 25.13.1.1, 26.13.1.1,27.13.1.1, 28.13.1.1, 29.13.1.1, 30.13.1.1, 31.13.1.1, 32.13.1.1,33.13.1.1, 34.13.1.1, 35.13.1.1, 36.13.1.1, 37.13.1.1, 38.13.1.1,39.13.1.1, 40.13.1.1, 1.14.1.1, 2.14.1.1, 3.14.1.1, 4.14.1.1, 5.14.1.1,6.14.1.1, 7.14.1.1, 8.14.1.1, 9.14.1.1, 10.14.1.1, 11.14.1.1, 12.14.1.1,13.14.1.1, 14.14.1.1, 15.14.1.1, 16.14.1.1, 17.14.1.1, 18.14.1.1,19.14.1.1, 20.14.1.1, 21.14.1.1, 22.14.1.1, 23.14.1.1, 24.14.1.1,25.14.1.1, 26.14.1.1, 27.14.1.1, 28.14.1.1, 29.14.1.1, 30.14.1.1,31.14.1.1, 32.14.1.1, 33.14.1.1, 34.14.1.1, 35.14.1.1, 36.14.1.1,37.14.1.1, 38.14.1.1, 39.14.1.1, 40.14.1.1, 1.15.1.1, 2.15.1.1,3.15.1.1, 4.15.1.1, 5.15.1.1, 6.15.1.1, 7.15.1.1, 8.15.1.1, 9.15.1.1,10.15.1.1, 11.15.1.1, 12.15.1.1, 13.15.1.1, 14.15.1.1, 15.15.1.1,16.15.1.1, 17.15.1.1, 18.15.1.1, 19.15.1.1, 20.15.1.1, 21.15.1.1,22.15.1.1, 23.15.1.1, 24.15.1.1, 25.15.1.1, 26.15.1.1, 27.15.1.1,28.15.1.1, 29.15.1.1, 30.15.1.1, 31.15.1.1, 32.15.1.1, 33.15.1.1,34.15.1.1, 35.15.1.1, 36.15.1.1, 37.15.1.1, 38.15.1.1, 39.15.1.1,40.15.1.1, 1.16.1.1, 2.16.1.1, 3.16.1.1, 4.16.1.1, 5.16.1.1, 6.16.1.1,7.16.1.1, 8.16.1.1, 9.16.1.1, 10.16.1.1, 11.16.1.1, 12.16.1.1,13.16.1.1, 14.16.1.1, 15.16.1.1, 16.16.1.1, 17.16.1.1, 18.16.1.1,19.16.1.1, 20.16.1.1, 21.16.1.1, 22.16.1.1, 23.16.1.1, 24.16.1.1,25.16.1.1, 26.16.1.1, 27.16.1.1, 28.16.1.1, 29.16.1.1, 30.16.1.1,31.16.1.1, 32.16.1.1, 33.16.1.1, 34.16.1.1, 35.16.1.1, 36.16.1.1,37.16.1.1, 38.16.1.1, 39.16.1.1, 40.16.11, 1.17.1.1, 2.17.1.1, 3.17.1.1,4.17.1.1, 5.17.1.1, 6.17.1.1, 7.17.1.1, 8.17.1.1, 9.17.1.1, 10.17.1.1,11.17.1.1, 12.17.1.1, 13.17.1.1, 14.17.1.1, 15.17.1.1, 16.17.1.1,17.17.1.1, 18.17.1.1, 19.17.1.1, 20.17.1.1, 21.17.1.1, 22.17.1.1,23.17.1.1, 24.17.1.1, 25.17.1.1, 26.17.1.1, 27.17.1.1, 28.17.1.1,29.17.1.1, 30.17.1.1, 31.17.1.1, 32.17.1.1, 33.17.1.1, 34.17.1.1,35.17.1.1, 36.17.1.1, 37.17.1.1, 38.17.1.1, 39.17.1.1, 40.17.1.1,1.18.1.1, 2.18.1.1, 3.18.1.1, 4.18.1.1, 5.18.1.1, 6.18.1.1, 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22.22.3.5, 23.22.3.5, 24.22.3.5,25.22.3.5, 26.22.3.5, 27.22.3.5, 28.22.3.5, 29.22.3.5, 30.22.3.5,31.22.3.5, 32.22.3.5, 33.22.3.5, 34.22.3.5, 35.22.3.5, 36.22.3.5,37.22.3.5, 38.22.3.5, 39.22.3.5, 40.22.3.5, 1.23.3.5, 2.23.3.5,3.23.3.5, 4.23.3.5, 5.23.3.5, 6.23.3.5, 7.23.3.5, 8.23.3.5, 9.23.3.5,10.23.3.5, 11.23.3.5, 12.23.3.5, 13.23.3.5, 14.23.3.5, 15.23.3.5,16.23.3.5, 17.23.3.5, 18.23.3.5, 19.23.3.5, 20.23.3.5, 21.23.3.5,22.23.3.5, 23.23.3.5, 24.23.3.5, 25.23.3.5, 26.23.3.5, 27.23.3.5,28.23.3.5, 29.23.3.5, 30.23.3.5, 31.23.3.5, 32.23.3.5, 33.23.3.5,34.23.3.5, 35.23.3.5, 36.23.3.5, 37.23.3.5, 38.23.3.5, 39.23.3.5,40.23.3.5, 1.24.3.5, 2.24.3.5, 3.24.3.5, 4.24.3.5, 5.24.3.5, 6.24.3.5,7.24.3.5, 8.24.3.5, 9.24.3.5, 10.24.3.5, 11.24.3.5, 12.24.3.5,13.24.3.5, 14.24.3.5, 15.24.3.5, 16.24.3.5, 17.24.3.5, 18.24.3.5,19.24.3.5, 20.24.3.5, 21.24.3.5, 22.24.3.5, 23.24.3.5, 24.24.3.5,25.24.3.5, 26.24.3.5, 27.24.3.5, 28.24.3.5, 29.24.3.5, 30.24.3.5,31.24.3.5, 32.24.3.5, 33.24.3.5, 34.24.3.5, 35.24.3.5, 36.24.3.5,37.24.3.5, 38.24.3.5, 39.24.3.5, 40.24.3.5, 1.25.3.5, 2.25.3.5,3.25.3.5, 4.25.3.5, 5.25.3.5, 6.25.3.5, 7.25.3.5, 8.25.3.5, 9.25.3.5,10.25.3.5, 11.25.3.5, 12.25.3.5, 13.25.3.5, 14.25.3.5, 15.25.3.5,16.25.3.5, 17.25.3.5, 18.25.3.5, 19.25.3.5, 20.25.3.5, 21.25.3.5,22.25.3.5, 23.25.3.5, 24.25.3.5, 25.25.3.5, 26.25.3.5, 27.25.3.5,28.25.3.5, 29.25.3.5, 30.25.3.5, 31.25.3.5, 32.25.3.5, 33.25.3.5,34.25.3.5, 35.25.3.5, 36.25.3.5, 37.25.3.5, 38.25.3.5, 39.25.3.5,40.25.3.5, 1.26.3.5, 2.26.3.5, 3.26.3.5, 4.26.3.5, 5.26.3.5, 6.26.3.5,7.26.3.5, 8.26.3.5, 9.26.3.5, 10.26.3.5, 11.26.3.5, 12.26.3.5,13.26.3.5, 14.26.3.5, 15.26.3.5, 16.26.3.5, 17.26.3.5, 18.26.3.5,19.26.3.5, 20.26.3.5, 21.26.3.5, 22.26.3.5, 23.26.3.5, 24.26.3.5,25.26.3.5, 26.26.3.5, 27.26.3.5, 28.26.3.5, 29.26.3.5, 30.26.3.5,31.26.3.5, 32.26.3.5, 33.26.3.5, 34.26.3.5, 35.26.3.5, 36.26.3.5,37.26.3.5, 38.26.3.5, 39.26.3.5, 40.26.3.5, 1.27.3.5, 2.27.3.5,3.27.3.5, 4.27.3.5, 5.27.3.5, 6.27.3.5, 7.27.3.5, 8.27.3.5, 9.27.3.5,10.27.3.5, 11.27.3.5, 12.27.3.5, 13.27.3.5, 14.27.3.5, 15.27.3.5,16.27.3.5, 17.27.3.5, 18.27.3.5, 19.27.3.5, 20.27.3.5, 21.27.3.5,22.27.3.5, 23.27.3.5, 24.27.3.5, 25.27.3.5, 26.27.3.5, 27.27.3.5,28.27.3.5, 29.27.3.5, 30.27.3.5, 31.27.3.5, 32.27.3.5, 33.27.3.5,34.27.3.5, 35.27.3.5, 36.27.3.5, 37.27.3.5, 38.27.3.5, 39.27.3.5,40.27.3.5, 1.28.3.5, 2.28.3.5, 3.28.3.5, 4.28.3.5, 5.28.3.5, 6.28.3.5,7.28.3.5, 8.28.3.5, 9.28.3.5, 10.28.3.5, 11.28.3.5, 12.28.3.5,13.28.3.5, 14.28.3.5, 15.28.3.5, 16.28.3.5, 17.28.3.5, 18.28.3.5,19.28.3.5, 20.28.3.5, 21.28.3.5, 22.28.3.5, 23.28.3.5, 24.28.3.5,25.28.3.5, 26.28.3.5, 27.28.3.5, 28.28.3.5, 29.28.3.5, 30.28.3.5,31.28.3.5, 32.28.3.5, 33.28.3.5, 34.28.3.5, 35.28.3.5, 36.28.3.5,37.28.3.5, 38.28.3.5, 39.28.3.5, 40.28.3.5, 1.29.3.5, 2.29.3.5,3.29.3.5, 4.29.3.5, 5.29.3.5, 6.29.3.5, 7.29.3.5, 8.29.3.5, 9.29.3.5,10.29.3.5, 11.29.3.5, 12.29.3.5, 13.29.3.5, 14.29.3.5, 15.29.3.5,16.29.3.5, 17.29.3.5, 18.29.3.5, 19.29.3.5, 20.29.3.5, 21.29.3.5,22.29.3.5, 23.29.3.5, 24.29.3.5, 25.29.3.5, 26.29.3.5, 27.29.3.5,28.29.3.5, 29.29.3.5, 30.29.3.5, 31.29.3.5, 32.29.3.5, 33.29.3.5,34.29.3.5, 35.29.3.5, 36.29.3.5, 37.29.3.5, 38.29.3.5, 39.29.3.5 and40.29.3.5.

Table 2 lists a group of cyclic nucleotide analogs of structure Iwherein Z forms a heterocyclic ring containing the phosphorus atom ofthe phosphonate group and two oxygen atoms as shown. Hydrolysis of theL¹ group linked to the phosphorus atom and subsequent ring hydrolysisresults in formation of an HPMP nucleoside such as HPMPC(1-(2-phosphonomethoxy-3-hydroxypropyl)-cytosine).

TABLE 2 1¹*  1 —NH—CH₂—C(O)—OR⁴  2 —NH—CH(CH₃)—C(O)—OR⁴  3—NH—CH(CH₃)₂—C(O)—OR⁴  4 —NH—CH(CH(CH₃)₂)-C(O)-OR⁴  5—NH—CH(CH₃)(CH₃)_(2—C(O)—OR) ⁴  6 —N—CH₂—CH₂—CH₂—CH—C(O)—OR⁴  7—NH—CH(CH₂—C₆H₅)—C(O)—OR⁴  8 —NH—CH(CH₂—C₈NH₆)—C(O)—OR⁴  9—NH—CH(CH₂—CH₂—S—CH₃)—C(O)—OR⁴ 10 —NH—CH(CH₂OH)—C(O)—OR⁴ 11—NH—CH(CH(OH)(CH₃)—C(O)—OR⁴ 12 —NH—CH(—CH₂SH)—C(O)—OR⁴ 13—NH—CH(CH₂—C₆H₅OH)—C(O)—OR⁴ 14 —NH—CH(CH₂—C(O)—NH₂)—C(O)—OR⁴ 15—NH—CH(CH₂—CH₂—C(O)—NH₂)—C(O)—OR⁴ 16 —NH—CH(CH₂C(O)OR⁴)—C(O)—OR⁴ 17—NH—CH(CH₂CH₂C(O)OR⁴)—C(O)—OR⁴ 18 —NH—CH(CH₂CH₂CH₂CH₂NH₂)—C(O)—OR⁴ 19—NH—CH(CH₂CH₂CH₂NHC(NH)(NH₂))—C(O)—OR⁴ 20 —NH—CH(CH₂C₃N₂H₃)—C(O)—OR⁴ 21—NH—CH(CH₂CH₂CH₂NH₂)—CH₂—C(O)—OR⁴ 22—NH—CH(CH₂CH₂CH₂CH₂NH₂)—CH₂—C(O)—OR⁴ 23—NH—CH(CH₂CH₂NHC(NH)(NH₂))—CH₂—C(O)—OR⁴ 24 —NH—CH(C(O)OR⁴)—CH₂—C(O)—OR⁴25 —NH—CH(CH₂C(O)OR⁴)—CH₂—C(O)—OR⁴ 26 —NH—CH(CH₂CH₂C(O)OR⁴)—CH₂—C(O)—OR⁴Z-B**

B  1. adenin-9-yl  2. guanin-9-yl  3. cytosin-1-yl  4.2,6-diaminopurin-9-yl  5. 2-aminopurin-9-yl  6. 6-azacytosin-1-yl  7.1-deazaadenin-9-yl  8. 3-deazaadenin-9-yl  9. 8-azaadenin-9-yl 10.7-deaza-8-azaapdenin-9-yl *See Table 1 footnote. **See Table 1 footnote.^(#)See Table 1 footnote.Compounds listed in Table 2 are designated herein by numbers assigned toL¹, Z and B according to the following convention, L.Z.B. Thus,compounds 1.1.3 and 1.2.3 represent, when R4 is H, glycinyl cyclic HPMPCand alanyl cyclic HPMPC. Exemplary compounds include 1.1.1, 1.12,1.1.3,1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, 2.1.1, 2.1.2,2.1.3, 2.1.4, 2.1.5, 2.1.6, 2.1.7, 2.1.8, 2.1.9, 2.1.10, 3.1.1, 3.1.2,3.1.3, 3.1.4, 3.1.5, 3.1.6, 3.1.7, 3.1.8, 3.1.9, 3.1.10, 4.1.1, 4.1.2,4.1.3, 4.1.4, 4.1.5, 4.1.6, 4.1.7, 4.1.8, 4.1.9, 4.1.10, 5.1.1, 5.1.2,5.1.3, 5.1.4, 5.1.5, 5.1.6, 5.1.7, 5.1.8, 5.1.9, 5.1.10, 6.1.1, 6.1.2,6.1.3, 6.1.4, 6.1.5, 6.1.6, 6.1.7, 6.1.8, 6.1.9, 6.1.10, 7.1.1, 7.1.2,7.1.3, 7.1.4, 7.1.5, 7.1.6, 7.1.7, 7.1.8, 7.1.9, 7.1.10, 8.1.1, 8.1.2,8.1.3, 8.1.4, 8.1.5, 8.1.6, 8.1.7, 8.1.8, 8.1.9, 8.1.10, 9.1.1, 9.1.2,9.1.3, 9.1.4, 9.1.5, 9.1.6, 9.1.7, 9.1.8 , 9.1.9, 9.1.10, 10.1.1,10.1.2, 10.1.3, 10.1.4, 10.1.5, 10.1.6, 10.1.7, 10.1.8, 10.1.9, 10.1.10,11.1.1, 11.1.2, 11.1.3, 11.1.4, 11.1.5, 11.1.6, 11.1.7, 11.1.8, 11.1.9,11.1.10, 12.1.1, 12.1.2, 12.1.3, 12.1.4, 12.1.5, 12.1.6, 12.1.7, 12.1.8,12.1.9, 12.1.10, 14.1.1, 13.1.2, 13.1.3, 13.1.4, 13.1.5, 13.1.6, 13.1.7,13.1.8, 13.1.9, 13.1.10, 14.1.1, 14.1.2, 14.1.3, 14.1.4, 14.1.5, 14.1.6,14.1.7, 14.1.8, 14.1.9, 14.1.10, 15.1.1, 15.1.2, 15.1.3, 15.1.4, 15.1.5,15.1.6, 15.1.7, 15.1.8, 15.1.9, 15.1.10, 16.1.1, 16.1.2, 16.1.3, 16.1.4,16.1.5, 16.1.6, 16.1.7, 16.1.8, 16.1.9, 16.1.10, 17.1.1, 17.1.2, 17.1.3,17.1.4, 17.1.5, 17.1.6, 17.1.7, 17.1.8, 17.1.9, 17.1.10, 18.1.1, 18.1.2,18.1.3, 18.1.4, 18.1.5, 18.1.6, 18.1.7, 18.1.8, 18.1.9, 18.1.10, 19.1.1,19.1.2, 19.1.3, 19.1.4, 19.1.5, 19.1.6, 19.1.7, 19.1.8, 19.1.9, 19.1.10,20.1.1, 20.1.2, 20.1.3, 20.1.4, 20.1.5, 20.1.6, 20.1.7, 20.1.8, 20.1.9,20.1.10, 21.1.1, 21.1.2, 21.1.3, 21.1.4, 21.1.5, 21.1.6, 21.1.7, 21.1.8,21.1.9, 21.1.10, 22.1.1, 22.1.2, 22.1.3, 2.1.4, 22.1.5, 22.1.6, 22.1.7,22.1.8, 22.1.9, 22.1.10, 23.1.1, 23.1.2, 23.1.3, 23.1.4, 23.1.5, 23.1.6,23.1.7, 23.1.8, 23.1.9, 23.1.10, 24.1.1, 24.1.2, 24.1.3, 24.1.4, 24.1.5,24.1.6, 24.1.7, 24.1.8, 24.1.9, 24.1.10, 25.1.1, 25.1.2, 25.1.3, 25.1.4,25.1.5, 25.1.6, 25.1.7, 25.1.8, 25.1.9, 25.1.10, 26.1.1, 26.1.2, 26.1.3,26.1.4, 26.1.5, 26.1.6, 26.1.7, 26.1.8,26.1.9, 26.1.10, 27.1.1, 27.1.2,27.1.3, 27.1.4, 27.1.5, 27.1.6, 27.1.7, 27.1.8, 27.1.9, 27.1.10, 28.1.1,28.1.2, 28.1.3, 28.1.4, 28.1.5, 28.1.6, 28.1.7, 28.1.8, 28.1.9, 28.1.10,1.2.1, 1.2.2, 1.2.3, 1.2.4, 1.2.5, 1.2.6, 1.2.7, 1.2.8, 1.2.9, 1.2.10,2.2.1, 2.2.2, 2.2.3, 2.2.4, 2.2.5, 2.2.6, 2.2.7, 2.2.8, 2.2.9, 2.2.10,3.2.1, 3.2.2, 3.2.3, 3.2.4, 3.2.5, 3.2.6, 3.2.7, 3.2.8, 3.2.9, 3.2.10,4.2.1, 4.2.2, 4.2.3, 4.2.4, 4.2.5, 4.2.6, 4.2.7, 4.2.8, 4.2.9, 4.2.10,5.2.1, 5.2.2, 5.2.3, 5.2.4, 5.2.5, 5.2.6, 5.2.7, 5.2.8, 5.2.9, 5.2.10,6.2.1, 6.2.2, 6.2.3, 6.2.4, 6.2.5, 6.2.6, 6.2.7, 6.2.8, 6.2.9, 6.2.10,7.2.1, 7.2.2, 7.2.3, 7.2.4, 7.2.5, 7.2.6, 7.2.7, 7.2.8, 7.2.9, 7.2.10,8.2.1, 8.2.2, 8.2.3, 8.2.4, 8.2.5, 8.2.6, 8.2.7, 8.2.8, 8.2.9, 8.2.10,9.2.1, 9.2.2, 9.2.3, 9.2.4, 9.2.5, 9.2.6,9.2.7, 9.2.8, 9.2.9, 9.2.10,10.2.1, 10.2.2, 10.2.3, 10.2.4, 10.2.5, 10.2.6, 10.2.7, 10.2.8, 10.2.9,10.2.10, 11.2.1, 11.2.2, 11.2.3, 11.2.4, 11.2.5, 11.2.6, 11.2.7, 11.2.8,11.2.9, 11.2.10, 12.2.1, 12.2.2, 12.2.3, 12.2.4, 12.2.5, 12.2.6, 12.2.7,12.2.8, 12.2.9, 12.2.10, 13.2.1, 13.2.2, 13.2.3, 13.2.4, 13.2.5, 13.2.6,13.2.7, 13.2.8, 13.2.9, 13.2.10, 14.2.1, 14.2.2, 14.2.3, 14.2.4, 14.2.5,14.2.6, 14.2.7, 14.2.8, 14.2.9, 14.2.10, 15.2.1, 15.2.2, 15.2.3, 15.2.4,15.2.5, 15.2.6, 15.2.7, 15.2.8, 15.2.9, 15.2.10, 16.2.1, 16.2.2, 16.2.3,16.2.4, 16.2.5, 16.2.6, 16.2.7, 16.2.8, 16.2.9, 16.2.10, 17.2.1, 17.2.2,17.2.3, 17.2.4, 17.2.5, 17.2.6, 17.2.7, 17.2.8, 17.2.9, 17.2.10, 18.2.1,18.2.2, 18.2.3, 18.2.4, 18.2.5, 18.2.6, 18.2.7, 18.2.8, 18.2.9, 18.2.10,19.2.1, 19.2.2, 19.2.3, 19.2.4, 19.2.5, 19.2.6, 19.2.7, 19.2.8, 19.2.9,19.2.10, 20.2.1, 20.2.2, 20.2.3, 20.2.4, 20.2.5, 20.2.6, 20.2.7, 20.2.8,20.2.9, 20.2.10, 21.2.1, 21.2.2, 21.2.3, 21.2.4, 21.2.5, 21.2.6, 21.2.7,21.2.8, 21.2.9, 21.2.10, 22.2.1, 22.2.2, 22.2.3,22.2.4, 22.2.5, 22.2.6,22.2.7, 22.2.8, 22.2.9, 22.2.10, 23.2.1, 23.2.2, 23.2.3, 23.2.4, 23.2.5,23.2.6, 23.2.7, 23.2.8, 23.2.9, 23.2.10, 24.2.1, 24.2.2, 24.2.3, 24.2.4,24.2.5, 24.2.6, 24.2.7, 24.2.8, 24.2.9, 24.2.10, 25.2.1, 25.2.2, 25.2.3,25.2.4, 25.2.5, 25.2.6, 25.2.7, 25.2.8, 25.2.9, 25.2.10, 26.2.1, 26.2.2,26.2.3, 26.2.4, 26.2.5, 26.2.6, 26.2.7, 26.2.8, 26.2.9 and 26.2.10.Table 3 lists a group of cyclic nudceotide analog amidates of structureI wherein L¹ forms a heterocyclic ring containing the phosphorus atom ofthe phosphonate group. Hydrolysis of the heterocyclic ring linkedthrough the phosphorus atom results in formation of a phosphonatenucleotide analog such as HPMPC, PMEA, PMEG or PMWDAP depending on the Zgroup that is present.

TABLE 3 L¹  1 —NH—CH₂—C(O)—O—CH₂—O—  2 —NH—CH(CH₃)—C(O)—O—CH₂—O—  3—NH—CH(CH₃)₂—C(O)—O—CH₂—O—  4 —NH—CH(CH(CH₃)₂)—C(O)—O—CH₂—O—  5—NH—CH(CH₃)(CH₃)₂—C(O)—O—CH₂—O—  6 —NH—CH₂—CH₂—CH₂—CH—C(O)—O—CH₂—O—  7—NH—CH(CH₂—C₆H₅)—C(O)—O—CH₂—O—  8 —NH—CH(CH₂—C₈NH₆)—C(O)—O—CH₂—O—  9—NH—CH(CH₂—CH₂—S—CH₃)—C(O)—O— 10 —NH—CH(CH₂OH)—C(O)—O—CH₂—O— 11—NH—CH(CH(OH)(CH₃)—C(O)—O—CH₂—O— 12 —NH—CH(—CH₂SH)—C(O)—O—CH₂—O— 13—NH—CH(CH2—C₆H₅OH)—C(O)—O—CH₂—O— 14 —NH—CH(CH₂—C(O)—NH₂)—C(O)—O—CH₂—O—15 —NH—CH(CH₂—CH₂—C(O)—NH₂)—C(O)—O—CH₂—O— 16—NH—CH(CH₂C(O)OR⁴)—C(O)—O—CH₂—O— 17 —NH—CH(CH₂CH₂C(O)OR⁴)—C(O)—O—CH₂—O—18 —NH—CH(CH₂CH₂CH₂CH₂NH₂)—C(O)—O—CH₂—O— 19—NH—CH(CH₂CH₂CH₂NHC(NH)(NH₂))—C(O)—O—CH₂—O— 20—NH—CH(CH₂C₃N₂H₃)—C(O)—O—CH₂—O— 21—NH—CH(CH₂CH₂CH₂NH₂)—CH₂—C(O)—O—CH₂—O— 22—NH—CH(CH₂CH₂CH₂CH₂NH₂)—CH₂—C(O)—O—CH₂—O— 23—NH—CH(CH₂CH₂NHC(NH)(NH₂))—CH₂—C(O)—O— CH₂—O— 24—NH—CH(C(O)OR⁴)—CH₂—C(O)—O—CH₂—O— 25 —NH—CH(CH₂C(O)OR⁴)—CH₂—C(O)—O— 26—NH—CH(CH₂CH₂C(O)OR⁴)—CH₂—C(O)—O—CH₂—O— 27 —NH—CH₂—C(O)—O—CH(C(O)OR⁴)—N—28 —NH—CH(CH₃)—C(O)—O—CH(C(O)OR⁴)—N— B  1 adenin-9-yl  2 guanin-9-yl  3cytosin-1-yl  4 2,6-diaminopurin-9-yl  5 2-aminopurin-9-yl  66-azacytosin-1-yl  7 1-deazaadenin-9-yl  8 3-deazaadenin-9-yl  98-azaadenin-9-yl 10 7-deaza-8-azaadenin-9-yl Z-B**  1 —CH₂—O—CH₂—CH₂—B 2 —CH₂—O—C^(#)H(CH₂—OR⁴)—CH₂—B  3 —CH₂—O—C^(#)H(CH₃)—CH₂—B  4—CH₂—O—C^(#)H(CH₂F)—CH₂—B  5 —CH₂—O—C^(#)H(CH═CH₂)—CH₂—B  6—CH₂—O—C^(#)H(CH₂N₃)—CH₂—B * - See Table 1 footnote; the terminalnitrogen and oxygen or nitrogen atoms are both linked to the phosphorusatom of the phosphonate group. **See Table 1 footnote. ^(#)See Table 1footnote.Compounds listed in Table 3 are designated herein by numbers assigned toL¹, Z and B according to the following convention, L¹.Z.B. Thus,compounds 1.1.1 and 2.3.4 represent compounds designated cyclicglycinylPMEA and cyclic alanylPMPDAP. Exemplary compounds include 1.1.1,1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, 2.1.1,2.1.2, 2.1.3, 2.1.4, 2.1.5, 2.1.6, 2.1.7, 2.1.8, 2.1.9, 2.1.10, 3.1.1,3.1.2, 3.1.3, 3.1.4, 3.1.5, 3.1.6, 3.1.7, 3.1.8, 3.1.9, 3.1.10, 4.1.1,4.1.2, 4.1.3, 4.1.4, 4.1.5, 4.1.6, 4.1.7, 4.1.8, 4.1.9, 4.1.10, 5.1.1,5.1.2, 5.1.3, 5.1.4, 5.1.5, 5.1.6, 5.1.7, 5.1.8, 5.1.9, 5.1.10, 6.1.1,6.1.2, 6.1.3, 6.1.4, 6.1.5, 6.1.6, 6.1.7, 6.1.8, 6.1.9, 6.1.10, 7.1.1,7.1.2, 7.1.3, 7.1.4, 7.1.5, 7.1.6, 7.1.7, 7.1.8, 7.1.9, 7.1.10, 8.1.1,8.1.2, 8.1.3, 8.1.4, 8.1.5, 8.1.6, 8.1.7,8.1.8, 8.1.9,8.1.10,9.1.1,9.1.2i 9.1.3,9.1.4, 9.1.5,9.1.6, 9.1.7,9.1.8,9.1.9, 9.1.10, 10.1.1,10.1.2, 10.1.3, 10.1.4, 10.1.5, 10.1.6, 10.1.7, 10.1.8, 10.1.9, 10.1.10,11.1.1, 11.1.2, 11.1.3, 11.1.4, 11.1.5, 11.1.6, 11.1.7, 11.1.8, 11.1.9,11.1.10, 12.1.1, 12.1.2, 12.1.3, 12.1.4, 12.1.5, 12.1.6, 12.1.7, 12.1.8,12.1.9, 12.1.10, 13.1.1, 13.1.2, 13.1.3, 13.1.4, 13.1.5, 13.1.6, 13.1.7,13.1.8, 13.1.9, 13.1.10, 14.1.1, 14.1.2, 14.1.3, 14.1.4, 14.1.5, 14.1.6,14.1.7, 14.1.8, 14.1.9, 14.1.10, 15.1.1, 15.1.2, 15.1.3, 15.1.4, 15.1.5,15.1.6, 15.1.7, 15.1.8, 15.1.9, 15.1.10, 16.1.1, 16.1.2, 16.1.3, 16.1.4,16.1.5, 16.1.6, 16.1.7, 16.1.8, 16.1.9, 16.1.10, 17.1.1, 17.1.2, 17.1.3,17.1.4, 17.1.5, 17.1.6, 17.1.7, 17.1.8, 17.1.9, 17.1.10, 18.1.1, 18.1.2,18.1.3, 18.1.4, 18.1.5, 18.1.6, 18.1.7, 18.1.8, 18.1.9, 18.1.10, 19.1.1,19.1.2, 19.1.3, 19.1.4, 19.1.5, 19.1.6, 19.1.7, 19.1.8, 19.1.9, 19.1.10,20.1.1, 20.1.2, 20.1.3, 20.1.4, 20.1.5, 20.1.6, 20.1.7, 20.1.8, 20.1.9,20.1.10, 21.1.1, 21.1.2, 21.1.3, 21.1.4, 21.1.5, 21.1.6, 21.1.7, 21.1.8,21.1.9, 21.1.10, 22.1.1, 22.1.2, 22.1.3, 22.1.4, 22.1.5, 22.1.6, 22.1.7,22.1.8, 22.1.9, 22.1.10, 23.1.1, 23.1.2, 23.1.3, 23.1.4, 23.1.5, 23.1.6,23.1.7, 23.1.8, 23.1.9, 23.1.10, 24.1.1, 24.1.2, 24.1.3, 24.1.4, 24.1.5,24.1.6, 24.1.7, 24.1.8, 24.1.9, 24.1.10,25.1.1, 25.1.2, 25.1.3, 25.1.4,25.1.5, 25.1.6, 25.1.7, 25.1.8, 25.1.9, 25.1.10, 26.1.1, 26.1.2, 26.1.3,26.1.4, 26.1.5, 26.1.6, 26.1.7, 26.1.8, 26.1.9, 26.1.10, 27.1.1, 27.1.2,27.1.3, 27.1.4, 27.1.5, 27.1.6, 27.1.7, 27.1.8, 27.1.9, 27.1.10, 28.1.1,28.1.2, 28.1.3, 28.1.4, 28.1.5, 28.1.6, 28.1.7, 28.1.8, 28.1.9, 28.1.10,1.2.1, 1.2.2, 1.2.3, 1.2.4, 1.2.5, 1.2.6, 1.2.7, 1.2.8, 1.2.9, 1.2.10,2.2.1, 2.2.2, 2.2.3, 2.2.4, 2.2.5, 2.2.6, 2.2.7, 2.2.8, 2.2.9, 2.2.10,3.2.1, 3.2.2, 3.2.3, 3.2.4, 3.2.5, 3.2.6, 3.2.7, 3.2.8, 3.2.9, 3.2.10,4.2.1, 4.2.2, 4.2.3, 4.2.4, 4.2.5, 4.2.6, 4.2.7, 4.2.8, 4.2.9, 4.2.10,5.2.1, 5.2.2, 5.2.3, 5.2.4, 5.2.5, 5.2.6, 5.2.7, 5.2.8, 5.2.9, 5.2.10,6.2.1, 6.2.2, 6.2.3, 6.2.4, 6.2.5, 6.2.6, 6.2.7, 6.2.8, 6.2.9, 6.2.10,7.2.1, 7.2.2, 7.2.3, 7.2.4, 7.2.5, 7.2.6, 7.2.7, 7.2.8, 7.2.9, 7.2.10,8.2.1, 8.2.2, 8.2.3, 8.2.4, 8.2.5, 8.2.6, 8.2.7, 8.2.8, 8.2.9, 8.2.10,9.2.1, 9.2.2, 9.2.3, 9.2.4, 9.2.5, 9.2.6, 9.2.7, 9.2.8, 9.2.9, 9.2.10,10.2.1, 10.2.2, 10.2.3, 10.2.4, 10.2.5, 10.2.6, 10.2.7, 10.2.8, 10.2.9,10.2.10, 11.2.1, 11.2.2, 11.2.3, 11.2.4, 11.2.5, 11.2.6, 11.2.7, 11.2.8,11.2.9, 11.2.10, 12.2.1, 12.2.2, 12.2.3, 12.2.4, 12.2.5, 12.2.6, 12.2.7,12.2.8, 12.2.9, 12.2.10, 13.2.1, 13.2.2, 13.2.3, 13.2.4, 13.2.5, 13.2.6,13.2.7, 13.2.8, 13.2.9, 13.2.10, 14.2.1, 14.2.2, 14.2.3, 14.2.4, 14.2.5,14.2.6, 14.2.7, 14.2.8, 14.2.9, 14.2.10, 15.2.1, 15.2.2, 15.2.3, 15.2.4,15.2.5, 15.2.6, 15.2.7, 15.2.8, 15.2.9, 15.2.10, 16.2.1, 16.2.2, 16.2.3,16.2.4, 16.2.5, 16.2.6, 16.2.7, 16.2.8, 16.2.9, 16.2.10, 17.2.1, 17.2.2,17.2.3, 17.2.4, 17.2.5, 17.2.6, 17.2.7, 17.2.8, 17.2.9, 17.2.10, 18.2.1,18.2.2, 18.2.3, 18.2.4, 18.2.5, 18.2.6, 18.2.7, 18.2.8, 18.2.9, 18.2.10,19.2.1, 19.2.2, 19.2.3, 19.2.4, 19.2.5, 19.2.6, 19.2.7, 19.2.8, 19.2.9,19.2.10, 20.2.1, 20.2.2, 20.2.3, 20.2.4, 20.2.5, 20.2.6, 20.2.7, 20.2.8,20.2.9, 20.2.10, 21.2.1, 21.2.2, 21.2.3, 21.2.4, 21.2.5, 21.2.6, 21.2.7,21.2.8, 21.2.9, 21.2.10, 22.2.1, 22.2.2, 22.2.3, 22.2.4, 22.2.5, 22.2.6,22.2.7, 22.2.8, 22.2.9, 22.2.10, 23.2.1, 23.2.2, 23.2.3, 23.2.4, 23.2.5,23.2.6, 23.2.7, 23.2.8, 23.2.9, 23.2.10, 24.2.1, 24.2.2, 24.2.3, 24.2.4,24.2.5, 24.2.6, 24.2.7, 24.2.8, 24.2.9, 24.2.10, 25.2.1, 25.2.2, 25.2.3,25.2.4, 25.2.5, 25.2.6, 25.2.7, 25.2.8, 25.2.9, 25.2.10, 2.6.2.1,26.2.2, 26.2.3, 26.2.4, 26.2.5, 26.2.6, 26.2.7, 26.2.8, 26.2.9, 26.2.10,27.2.1, 27.2.2; 27.2.3, 27.2.4, 27.2.5, 27.2.6, 27.2.7, 27.2.8, 27.2.9,27.2.10, 28.2.1, 28.2.2, 28.2.3, 28.2.4, 28.2.5; 28.2.6, 28.2.7, 28.2.8,28.2.9, 28.2.10, 1.3.1, 1.3.2, 1.3.3, 1.3.4, 1.3.5, 1.3.6, 1.3.7, 1.3.8,1.3.9, 1.3.10, 2.3.1, 2.3.2, 2.3.3, 2.3.4, 2.3.5, 2.3.6, 2.3.7, 2.3.8,2.3.9, 2.3.10, 3.3.1, 3.3.2, 3.3.3, 3.3.4, 3.3.5, 3.3.6, 3.3.7, 3.3.8,3.3.9, 3.3.10, 4.3.1, 4.3.2, 4.3.3, 4.3.4, 4.3.5, 4.3.6, 4.3.7, 4.3.8,4.3.9, 4.3.10, 5.3.1, 5.3.2, 5.3.3, 5.3.4, 5.3.5, 5.3.6, 5.3.7, 5.3.8,5.3.9, 5.3.10, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8,6.3.9, 6.3.10, 7.3.1, 7.3.2, 7.3.3, 7.3.4, 7.3.5, 7.3.6, 7.3.7, 7.3.8,7.3.9, 7.3.10, 8.3.1; 8.3.2, 8.3.3, 8.3.4, 8.3.5, 8.3.6, 8.3.7, 8.3.8,8.3.9, 8.3.10, 9.3.1, 9.3.2, 9.3.3, 9.3.4, 9.3.5, 9.3.6, 9.3.7, 9.3.8,9.3.9, 9.3.10, 10.3.1, 10.3.2, 10.3.3, 10.3.4, 10.3.5, 10.3.6, 10.3.7,10.3.8, 10.3.9, 10.3.10, 11.3.1, 11.3.2, 11.3.3, 11.3.4, 11.3.5, 11.3.6,11.3.7, 11.3.8, 11.3.9, 11.3.10, 12.3.1, 12.3.2, 12.3.3, 12.3.4, 12.3.5,12.3.6, 12.3.7, 12.3.8, 12.3.9, 12.3.10, 13.3.1, 13.3.2, 13.3.3, 13.3.4,13.3.5, 13.3.6, 13.3.7, 13.3.8, 13.3.9, 13.3.10, 14.3.1, 14.3.2, 14.3.3,14.3.4, 14.3.5, 14.3.6, 14.3.7, 14.3.8, 14.3.9, 14.3.10, 15.3.1, 15.3.2,15.3.3, 15.3.4, 15.3.5, 15.3.6, 15.3.7, 15.3.8, 15.3.9, 15.3.10, 16.3.1,16.3.2, 16.3.3, 16.3.4, 16.3.5, 16.3.6, 16.3.7, 16.3.8, 16.3.9, 16.3.10,17.3.1, 17.3.2, 17.3.3, 17.3.4, 17.3.5, 17.3.6, 17.3.7, 17.3.8, 17.3.9,17.3.10, 18.3.1, 18.3.2, 18.3.3, 18.3.4, 18.3.5, 18.3.6, 18.3.7, 18.3.8,18.3.9, 18.3.10, 19.3.1, 19.3.2, 19.3.3, 19.3.4, 19.3.5, 19.3.6, 19.3.7,19.3.8, 19.3.9, 19.3.10, 20.3.1, 20.3.2, 20.3.3, 20.3.4, 20.3.5, 20.3.6,20.3.7, 20.3.8, 20.3.9, 20.3.10, 21.3.1, 21.3.2, 21.3.3, 21.3.4, 21.3.5,21.3.6, 21.3.7, 21.3.8, 21.3.9, 21.3.10, 22.3.1, 22.3.2, 22.3.3, 22.3.4,22.3.5, 22.3.6, 22.3.7, 22.3.8, 22.3.9, 22.3.10, 23.3.1, 23.3.2, 23.3.3,23.3.4, 23.3.5, 23.3.6, 23.3.7, 23.3.8, 23.3.9, 23.3.10, 24.3.1, 24.3.2,24.3.3, 24.3.4, 24.3.5, 24.3.6, 24.3.7, 24.3.8, 24.3.9, 24.3.10, 25.3.1,25.3.2, 25.3.3, 25.3.4, 25.3.5, 25.3.6, 25.3.7, 25.3.8, 25.3.9, 25.3.10,26.3.1, 26.3.2, 26.3.3, 26.3.4, 26.3.5, 26.3.6, 26.3.7, 26.3.8, 26.3.9,26.3.10, 27.3.1, 27.3.2, 27.3.3, 27.3.4, 27.3.5, 27.3.6,27.3.7, 27.3.8,27.3.9, 27.3.10, 28.3.1, 28.3.2, 28.3.3, 28.3.4, 28.3.5, 28.3.6, 28.3.7,28.3.8, 28.3.9 and 28.3.10.

Table 4 lists a group of cyclic nucleotide analogs of structure Iwherein a heterocyclic ring comprising L¹ and the phosphorus atom of thephosphonate group along with part of the Z-B substructure—O—CH₂—C#H(CH₂—)—CH₂—B. The unbonded O atom in the Z substructure islinked to L¹ through the α carboxyl group of the amino acid while theCH₂ moiety on the right side is linked to the P atom and the CH₂ moietylinked to the chiral carbon is linked to B (i.e.,-L¹-O—CH₂—C#H(CH₂—B)—O—CH₂—P(O)(L²)- with —P(O(L²)- and -L¹-linkedtogether). Hydrolysis of the compound results in formation of an HPMPnucleoside phosphonate. A related group of compounds comprises aheterocyclic ring linked through a side chain or other carboxyl groupinstead of through the carboxyl group linked to the cc carbon atom.Hydrolysis of these compounds also result in formation of an HPMPnucleoside phosphonate.

TABLE 4 L¹*-Z(B)—P(O)(L²)  1—NH—CH₂—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂—P(O)(L²)-  2—NH—CH(CH₃)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)-  3—NH—CH(CH₃)₂—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)-  4—NH—CH(CH(CH₃)₂)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)-  5—NH—CH(CH₃)(CH₃)₂—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)-  6—NH—CH₂—CH₂—CH₂—CH——C(O)—O—CH₂—C^(#)H(CH₂— B)—O—CH₂—P(O)(L²)-  7—NH—CH(CH₂—C₆H₅)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂ —P(O)(L²)-  8—NH—CH(CH₂—C₈NH₆)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂ —P(O)(L²)-  9—NH—CH(CH₂—CH₂—S—CH₃)—C(O)—O—CH₂—C^(#)H(CH₂—B)— O—CH₂—P(O)(L²)- 10—NH—CH(CH₂OH)—C(O)—O—CH₂—O—CH₂—C^(#)H(CH₂—B)—O— CH₂—P(O)(L²)- 11—NH—CH(CH(OH)(CH₃)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)- 12—NH—CH(—CH₂SH)—C(O)—O—CH₂—O—CH₂—C^(#)H(CH₂—B)—O —CH₂—P(O)(L²)- 13—NH—CH(CH2—C₆H₅OH)—C(O)O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)- 14—NH—CH(CH₂—C(O)—NH₂)—C(O)—O—CH₂—C^(#)H(CH₂—B)— O—CH₂—P(O)(L²)- 15—NH—CH(CH₂—CH₂—C(O)—NH₂)—C(O)—O—CH₂—C^(#)H(CH₂— B)—O—CH₂—P(O)(L²)- 16—NH—CH(CH₂C(O)OR⁴)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)- 17—NH—CH(CH₂CH₂C(O)OR⁴)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)- 18—NH—CH(CH₂CH₂CH₂CH₂NH₂)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂ —P(O)(L²)- 19—NH—CH(CH₂CH₂CH₂NHC(NH)(NH₂))—C(O)—O—CH₂—C^(#)H(CH₂—B)—O— CH₂—P(O)(L²)-20 —NH—CH(CH₂C₃N₂H₃)—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂— P(O)(L²)- 21—NH—CH(CH₃)—CH₂—C(O)—O—CH₂—C^(#)H(CH₂—B)—O—CH₂ —P(O)(L²)- 22—NH—CH(CH₂CH₂CH₂NH₂)—CH₂—C(O)—O—CH₂—C^(#)H(CH₂—B)—O— CH₂—P(O)(L²)- L²  1—NH—CH₂—C(O)—OR⁴  2 —NH—CH(CH₃)—C(O)—OR⁴  3 —O—CH₂—O—C(O)—C(CH₃)₃  4—O—CH₂C₆H₅  5 —O—C₆H₅  6 —O—CH(CH₃)₂  7 —NH—CH(CH₂C₆H₄)—C(O)—OR⁴  8 —OHB  1. adenin-9-yl  2. guanin-9-yl  3. cytosin-1-yl  4.2,6-diaminopurin-9-yl  5. 2-aminopurin-9-yl  6. 6-azacytosin-1-yl  7.1-deazaadenin-9-yl  8. 3-deazaadenin-9-yl  9. 8-azaadenin-9-yl 10.7-deaza-8-azaadenin-9-yl *See Table 1 footnote; the terminal nitrogenand phosphorus atoms are linked to each other.

Compounds listed in Table 4 are designated herein by numbers assigned toL¹, L², and B according to the following convention, L¹.L².B. All Zcorrespond to the esterified HPMP substructure moiety. Thus, compounds1.1.3 and 2.4.3 represent compounds designated “glycyl cyclic glycinylHPMPC” and “benzyl cyclic alanyl HPMPC” esters. Exemplary compoundsinclude 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1,1.6, 1.1.7, 1.1.8, 1.1.9,1.1.10, 2.1.1, 2.1.2, 2.1.3, 2.1.4, 2.1.5, 2.1.6, 2.1.7, 2.1.8, 2.1.9,2.1.10, 3.1.1, 3.1.2, 3.1.3, 3.1.4, 3.1.5, 3.1.6, 3.1.7, 3.1.8, 3.1.9,3.1.10, 4.1.1, 4.1.2, 4.1.3, 4.1.4, 4.1.5, 4.1.6, 4.1.7, 4.1.8, 4.1.9,4.1.10, 5.1.1, 5.1.2, 5.1.3, 5.1.4, 5.1.5, 5.1.6, 5.1.7, 5.1.8, 5.1.9,5.1.10,6.1.1, 6.1.2, 6.1.3, 6.1.4, 6.1.5, 6.1.6, 6.1.7, 6.1.8, 6.1.9,6.1.10, 7.1.1, 7.1.2, 7.1.3, 7.1.4, 7.1.5, 7.1.6, 7.1.7, 7.1.8, 7.1.9,7.1.10, 8.1.1, 8.1.2, 8.1.3, 8.1.4, 8.1.5, 8.1.6, 8.1.7, 8.1.8, 8.1.9,8.1.10, 9.1.1, 9.1.2, 9.1.3, 9.1.4, 9.1.5, 9.1.6, 9.1.7, 9.1.8, 9.1.9,9.1.10, 10.1.1, 10.1.2, 10.1.3, 10.1.4, 10.1.5, 10.1.6, 10.1.7, 10.1.8,10.1.9, 10.1.10, 11.1.1, 11.1.2, 11.1.3, 11.1.4, 11.1.5, 11.1.6, 11.1.7,11.1.8, 11.1.9, 11.1.10, 12.1.1, 12.1.2, 12.1.3, 12.1.4, 12.1.5, 12.1.6,12.1.7, 12.1.8, 12.1.9, 12.1.10, 13.1.1, 13.1.2, 13.1.3, 13.1.4, 13.1.5,13.1.6, 13.1.7, 13.1.8, 13.1.9, 13.1.10, 14.1.1, 14.1.2, 14.1.3, 14.1.4,14.1.5, 14.1.6, 14.1.7, 14.1.8, 14.1.9, 14.1.10, 15.1.1, 15.1.2, 15.1.3,15.1.4, 15.1.5, 15.1.6, 15.1.7, 15.1.8, 15.1.9, 15.1.10, 16.1.1, 16.1.2,16.1.3, 16.1.4, 16.1.5, 16.1.6, 16.1.7, 16.1.8, 16.1.9, 16.1.10, 17.1.1,17.1.2, 17.1.3, 17.1.4, 17.1.5, 17.1.6, 17.1.7, 17.1.8, 17.1.9, 17.1.10,18.1.1, 18.1.2, 18.1.3, 18.1.4, 18.1.5, 18.1.6, 18.1.7, 18.1.8, 18.1.9,18.1.10, 19.1.1, 19.1.2, 19.1.3, 19.1.4, 19.1.5, 19.1.6, 19.1.7, 19.1.8,19.1.9, 19.1.10, 20.1.1, 20.1.2, 20.1.3, 20.1.4, 20.1.5, 20.1.6, 20.1.7,20.1.8, 20.1.9, 20.1.10, 21.1.1, 21.1.2, 21.1.3, 21.1.4, 21.1.5, 21.1.6,21.1.7, 21.1.8, 21.1.9, 21.1.10, 22.1.1, 22.1.2, 22.1.3, 22.1.4, 22.1.5,22.1.6, 22.1.7, 22.1.8, 22.1.9, 22.1.10, 1.2.1, 1.2.2, 1.2.3, 1.2.4,1.2.5, 1.2.6, 1.2.7, 1.2.8, 1.2.9, 1.2.10, 2.2.1, 2.2.2, 2.2.3, 2.2.4,2.2.5, 2.2.6, 2.2.7, 2.2.8, 2.2.9, 2.2.10, 3.2.1, 3.2.2, 3.2.3, 3.2.4,3.2.5, 3.2.6, 3.2.7, 3.2.8, 3.2.9, 3.2.10, 4.2.1, 4.2.2, 4.2.3, 4.2.4,4.2.5, 4.2.6, 4.2.7, 4.2.8, 4.2.9, 4.2.10, 5.2.1, 5.2.2, 5.2.3, 5.2.4,5.2.5, 5.2.6, 5.2.7, 5.2.8, 5.2.9, 5.2.10, 6.2.1, 6.2.2, 6.2.3, 6.2.4,6.2.5, 6.2.6, 6.2.7, 6.2.8, 6.2.9, 6.2.10, 7.2.1, 7.2.2, 7.2.3, 7.2.4,7.2.5, 7.2.6, 7.2.7, 7.2.8, 7.2.9, 7.2.10, 8.2.1, 8.2.2, 8;2.3, 8.2.4,8.2.5, 8.2.6, 8.2.7, 8.2.8, 8.2.9, 8.2.10, 9.2.1, 9.2.2, 9.2.3, 9.2.4,9.2.5, 9.2.6, 9.2.7, 9.2.8, 9.2.9, 9.2.10, 10.2.1, 10.2.2, 10.2.3,10.2.4, 10.2.5, 10.2.6, 10.2.7, 10.2.8, 10.2.9, 10.2.10, 11.2.1, 11.2.2,11.2.3, 11.2.4, 11.2.5, 11.2.6, 11.2.7, 11.2.8, 11.2.9, 11.2.10, 12.2.1,12.2.2, 12.2.3, 12.2.4, 12.2.5, 12.2.6, 12.2.7, 12.2.8, 12.2.9, 12.2.10,13.2.1, 13.2.2, 13.2.3, 13.2.4, 13.2.5, 13.2.6, 13.2.7, 13.2.8, 13.2.9,13.2.10, 14.2.1, 14.2.2, 14.2.3, 14.2.4, 14.2.5, 14.2.6, 14.2.7, 14.2.8,14.2.9, 14.2.10, 15.2.1, 15.2.2, 15.2.3, 15.2.4, 15.2.5, 15.2.6, 15.2.7,15.2.8, 15.2.9, 15.2.10, 16.2.1, 16.2.1, 6.2.2, 16.2.3, 16.24, 16.2.5,16.2.6, 16.2.7, 16.2.8, 16.2.9, 16.2.10, 17.2.1, 17.2.2, 17.2.3, 17.2.4,17.2.5, 17.2.6, 17.2.7, 17.2.8, 17.2.9, 17.2.10, 18.2.1, 18.2.2, 18.2.3,18.2.4, 18.2.5, 18.2.6, 18.2.7, 18.2.8, 18.2.9, 18.2.10, 19.2.1, 19.2.2,19.2.3, 19.2.4, 19.2.5, 19.2.6, 19.2.7, 19.2.8, 19.2.9, 19.2.10, 20.2.1,20.2.2, 20.2.3, 20.2.4, 20.2.5, 20.2.6, 20.2.7, 20.2.8, 20.2.9, 20.2.10,21.2.1, 21.2.2, 21.2.3, 21.2.4, 21.2.5, 21.2.6, 21.2.7, 21.2.8, 21.2.9,21.2.10, 22.2.1, 22.2.2, 22.2.3, 22.2.4, 22.2.5, 22.2.6, 22.2.7, 22.2.8,22.2.9, 22.2.10, 1.3.1, 1.3.2, 1.3.3, 1.3.4, 1.3.5, 1.3.6, 1.3.7, 1.3.8,1.3.9, 1.3.10, 2.3.1, 2.3.2, 2.3.3, 2.3.4, 2.3.5, 2.3.6, 2.3.7, 2.3.8,2.3.9, 2.3.10, 3.3.1, 3.3.2, 3.3.3, 3.3.4, 3.3.5, 3.3.6, 3.3.7, 3.3.8,3.3.9, 3.3.10, 4.3.1, 4.3.2, 4.3.3, 4.3.4, 4.3.5, 4.3.6, 4.3.7, 4.3.8,4.3.9, 4.3.10, 5.3.1, 5.3.2, 5.3.3, 5.3.4, 5.3.5, 5.3.6, 5.3.7, 5.3.8,5.3.9, 5.3.10, 6.3.1, 6.3.2, 6.3.3, 6.3.4, 6.3.5, 6.3.6, 6.3.7, 6.3.8,6.3.9, 6.3.10, 7.3.1, 7.3.2, 7.3.3, 7.3.4, 7.3.5, 7.3.6, 7.3.7, 7.3.8,7.3.9, 7.3.10, 8.3.1, 8.3.2, 8.3.3, 8.3.4, 8.3.5, 8.3.6, 8.3.7, 8.3.8,8.3.9, 8.3.10, 9.3.1, 9.3.2, 9.3.3, 9.3.4, 9.3.5, 9.3.6, 9.3.7, 9.3.8,9.3.9, 9.3.10, 10.3.1, 10.3.2, 10.3.3, 10.3.4, 10.3.5, 10.3.6, 10.3.7,10.3.8, 10.3.9, 10.3.10, 11.3.1, 11.3.2, 11.3.3, 11.3.4, 11.3.5, 11.3.6,11.3.7, 11.3.8, 11.3.9, 11.3.10, 12.3.1, 12.3.2, 12.3.3, 12.3.4, 12.3.5,12.3.6, 12.3.7, 12.3.8, 12.3.9, 12.3.10, 13.3.1, 13.3.2, 13.3.3, 13.3.4,13.3.5, 13.3.6, 13.3.7, 13.3.8, 13.3.9, 13.3.10, 14.3.1, 14.3.2, 14.3.3,14.3.4, 14.3.5, 14.3.6, 14.3.7, 14.3.8, 14.3.9, 14.3.10, 15.3.1, 15.3.2,15.3.3, 15.3.4, 15.3.5, 15.3.6, 15.3.7, 15.3:8, 15.3.9, 15.3.10, 16.3.1,16.3.2, 16.3.3, 16.3.4, 16.3.5, 16.3.6, 16.3.7, 16.3.8, 16.3.9, 16.3.10,17.3.1, 17.3.2, 17.3.3, 17.3.4, 17.3.5, 17.3.6, 17.3.7, 17.3.8, 17.3.9,17.3.10, 18.3.1, 18.3.2, 18.3.3, 18.3.4, 18.3.5, 18.3.6, 18.3.7, 18.3.8,18.3.9, 18.3.10, 19.3.1, 19.3.2, 19.3.3, 19.3.4, 19.3.5, 19.3.6, 19.3.7,19.3.8, 19.3.9, 19.3.10, 20.3.1, 20.3.2, 20.3.3, 20.3.4, 20.3.5, 20.3.6,20.3.7, 20.3.8, 20.3.9, 20.3.10, 21.3.1, 21.3.2, 21.3.3, 21.3.4, 21.3.5,21.3.6, 21.3.7, 21.3.8, 21.3.9, 21.3.10, 22.3.1, 22.3.2, 22.3.3, 22.3.4,22.3.5, 22.3.6, 22.3.7, 22.3.8, 22.3.9, 22.3.10, 1.4.1, 1.4.2, 1.4.3,1.4.4, 1.4.5, 1.4.6, 1.4.7, 1.4.8, 1.4.9, 1.4.10, 2.4.1, 2.4.2, 2.4.3,2.4.4, 2.4.5, 2.4.6, 2.4.7, 2.4.8, 2.4.9, 2.4.10, 3.4.1, 3.4.2, 3.4.3,3.4.4, 3.4.5, 3.4.6, 3.4.7, 3.4.8, 3.4.9, 3.4.10, 4.4.1, 4.4.2, 4.4.3,4.4.4, 4.4.5, 4.4.6, 4.4.7, 4.4.8, 4.4.9, 4.4.10, 5.4.1, 5.4.2, 5.4.3,5.4.4, 5.4.5, 5.4.6, 5.4.7, 5.4.8, 5.4.9, 5.4.10, 6.4.1, 6.4.2, 6.4.3,6.4.4, 6.4.5, 6.4.6, 6.4.7, 6.4.8, 6.4.9, 6.4.10, 7.4.1, 7.4.2, 7.4.3,7.4.4, 7.4.5, 7.4.6, 7.4.7, 7.4.8, 7.4.9, 7.4.10, 8.4.1, 8.4.2, 8.4.3,8.4.4, 8.4.5, 8.4.6, 8.4.7, 8.4.8, 8.4.9, 8.4.10, 9.4.1, 9.4.2, 9.4.3,9.4.4, 9.4.5, 9.4.6, 9.4.7, 9.4.8, 9.4.9, 9.4.10, 10.4.1, 10.4.2,10.4.3, 10.4.4, 10.4.5, 10.4.6, 10.4.7, 10.4.8, 10.4.9, 10.4.10, 11.4.1,11.4.2, 11.4.3, 11.4.4, 11.4.5, 11.4.6, 11.4.7, 11.4.8, 11.4.9, 11.4.10,12.4.1, 12.4.2, 12.4.3, 12.4.4, 12.4.5, 12.4.6, 12.4.7, 12.4.8, 12.4.9,12.4.10, 13.4.1, 13.4.2, 13.4.3, 13.4.4, 13.4.5, 13.4.6, 13.4.7, 13.4.8,13.4.9, 13.4.10, 14.4.1, 14.4.2, 14.4.3, 14.4.4, 14.4.5, 14.4.6, 14.4.7,14.4.8, 14.4.9, 14.4.10, 15.4.1, 15.4.2, 15.4.3, 15.4.4, 15.4.5, 15.4.6,15.4.7, 15.4.8, 15.4.9, 15.4.10, 16.4.1, 16.4.2, 16.4.3, 16.4.4, 16.4.5,16.4.6, 16.4.7, 16.4.8, 16.4.9, 16.4.10, 17.4.1, 17.4.2, 17.4.3, 17.4.4,17.4.5, 17.4.6, 17.4.7, 17.4.8, 17.4.9, 17.4.10, 18.4.1, 18.4.2, 18.4.3,18.4.4, 18.4.5, 18.4.6, 18.4.7, 18.4.8, 18.4.9, 18.4.10, 19.4.1, 19.4.2,19.4.3, 19.4.4, 19.4.5, 19.4.6, 19.4.7, 19.4.8, 19.4.9, 19.4.10, 20.4.1,20.4.2, 20.4.3, 20.4.4, 20.4.5, 20.4.6, 20.4.7, 20.4.8, 20.4.9, 20.4.10,21.4.1, 21.4.2, 21.4.3, 21.4.4, 21.4.5, 21.4.6, 21.4.7, 21.4.8, 21.4.9,21.4.10, 22.4.1, 22.4.2, 22.4.3, 22.4.4, 22.4.5, 22.4.6, 22.4.7, 22.4.8,22.4.9, 22.4.10, 1.5.1, 1.5.2, 1.5.3, 1.5.4, 1.5.5, 1.5.6, 1.5.7, 1.5.8,1.5.9, 1.5.10, 2.5.1, 2.5.2, 2.5.3, 2.5.4, 2.5.5, 2.5.6, 2.5.7, 2.5.8,2.5.9, 2.5.10, 3.5.1, 3.5.2, 3.5.3, 3.5.4, 3.5.5, 3.5.6, 3.5.7, 3.5.8,3.5.9, 3.5.10, 4.5.1, 4.5.2, 4.5.3, 4.5.4, 4.5.5, 4.5.6, 4.5.7, 4.5.8,4.5.9, 4.5.10, 5.5.1, 5.5.2, 5.5.3, 5.5.4, 5.5.5, 5.5.6, 5.5.7, 5.5.8,5.5.9, 5.5.10, 6.5.1, 6.5.2, 6.5.3, 6.5.4, 6.5.5, 6.5.6, 6.5.7, 6.5.8,6.5.9, 6.5.10, 7.5.1, 7.5.2, 7.5.3, 7.5.4, 7.5.5, 7.5.6, 7.5.7, 7.5.8,7.5.9, 7.5.10, 8.5.1, 8.5.2, 8.5.3, 8.5.4, 8.5.5, 8.5.6, 8.5.7, 8.5.8,8.5.9, 8.5.10, 9.5.1, 9.5.2, 9.5.3, 9.5.4, 9.5.5, 9.5.6, 9.5.7, 9.5.8,9.5.9, 9.5.10, 10.5.1, 10.5.2, 10.5.3, 10.5.4, 10.5.5, 10.5.6, 10.5.7,10.5.8, 10.5.9, 10.5.10, 11.5.1, 11.5.2, 11.5.3, 11.5.4, 11.5.5, 11.5.6,11.5.7, 11.5.8, 11.5.9, 11.5.10, 12.5.1, 12.5.2, 12.5.3, 12.5.4, 12.5.5,12.5.6, 12.5.7, 12.5.8, 12.5.9, 12.5.10, 13.5.1, 13.5.2, 13.5.3, 13.5.4,13.5.5, 13.5.6, 13.5.7, 13.5.8, 13.5.9, 13.5.10, 14.5.1, 14.5.2, 14.5.3,14.5.4, 14.5.5, 14.5.6, 14.5.7, 14.5.8, 14.5.9, 14.5.10, 15.5.1, 15.5.2,15.5.3, 15.5.4, 15.5.5, 15.5.6, 15.5.7, 15.5.8, 15.5.9, 15.5.10, 16.5.1,16.5.2, 16.5.3, 16.5.4, 16.5.5, 16.5.6, 16.5.7, 16.5.8, 16.5.9, 16.5.10,17.5.1, 17.5.2, 17.5.3, 17.5.4, 17.5.5, 17.5.6, 17.5.7, 17.5.8, 17.5.9,17.5.10, 18.5.1, 18.5.2, 18.5.3, 18.5.4, 18.5.5, 18.5.6, 18.5.7, 18.5.8,18.5.9, 18.5.10, 19.5.1, 19.5.2, 19.5.3, 19.5.4, 19.5.5, 19.5.6, 19.5.7,19.5.8, 19.5.9, 19.5.10, 20.5.1, 20.5.2, 20.5.3, 20.5.4, 20.5.5, 20.5.6,20.5.7, 20.5.8, 20.5.9, 20.5.10, 21.5.1, 21.5.2, 21.5.3, 21.5.4, 21.5.5,21.5.6, 21.5.7, 21.5.8, 21.5.9, 21.5.10, 22.5.1, 22.5.2, 22.5.3, 22.5.4,22.5.5, 22.5.6, 22.5.7, 22.5.8, 22.5.9, 22.5.10, 1.6.1, 1.6.2, 1.6.3,1.6.4, 1.6.5, 1.6.6, 1.6.7, 1.6.8, 1.6.9, 1.6.10, 2.6.1, 2.6.2, 2.6.3,2.6.4, 2.6.5, 2.6.6, 2.6.7, 2.6.8, 2,6.9, 2.6.10, 3.6.1, 3.6.2, 3.6.3,3.6.4, 3.6.5, 3.6.6, 3.6.7, 3.6.8, 3.6.9, 3.6.10, 4.6.1, 4.6.2, 4.6.3,4.6.4, 4.6.5, 4.6.6, 4.6.7, 4.6.8, 4.6.9, 4.6.10, 5.6.1, 5.6.2, 5.6.3,5.6.4, 5.6.5, 5.6.6, 5.6.7, 5.6.8, 5.6.9, 5.6.10, 6.6.1, 6.6.2, 6.6.3,6.6.4, 6.6.5, 6.6.6, 6.6.7, 6.6.8, 6.6.9, 6.6.10, 7.6.1, 7.6.2, 7.6.3,7.6.4, 7.6.5, 7.6.6, 7.6.7, 7.6.8, 7.6.9, 7.6.10, 8.6.1, 8.6.2, 8.6.3,8.6.4, 8.6.5, 8.6.6, 8.6.7, 8.6.8, 8.6.9, 8.6.10, 9.6.1, 9.6.2, 9.6.3,9.6.4, 9.6.5, 9.6.6, 9.6.7, 9.6.8, 9.6.9, 9.6.10, 10.6.1, 10.6.2,10.6.3, 10.6.4, 10.6.5, 10.6.6, 10.6.7, 10.6.8, 10.6.9, 10.6.10, 11.6.1,11.6.2, 11.6.3, 11.6.4, 11.6.5, 11.6.6, 11.6.7, 11.6.8, 11.6.9, 11.6.10,12.6.1, 12.6.2, 12.6.3, 12.6.4, 12.6.5, 12.6.6, 12.6.7, 12.6.8, 12.6.9,12.6.10, 13.6.1, 13.6.2, 13.6.3, 13.6.4, 13.6.5, 13.6.6, 13.6.7, 13.6.8,13.6.9, 13.6.10, 14.6.1, 14.6.2, 14.6.3, 14.6.4, 14.6.5, 14.6.6, 14.6.7,14.6.8, 14.6.9, 14.6.10, 15.6.1, 15.6.2, 15.6.3, 15.6.4, 15.6.5, 15.6.6,15.6.7, 15.6.8, 15.6.9, 15.6.10, 16.6.1, 16.6.2, 16.6.3, 16.6.4, 16.6.5,16.6.6, 16.6.7, 16.6.8, 16.6.9, 16.6.10, 17.6.1, 17.6.2, 17.6.3, 17.6.4,17.6.5, 17.6.6, 17.6.7, 17.6.8, 17.6.9, 17.6.10, 18.6.1, 18.6.2, 18.6.3,18.6.4, 18.6.5, 18.6.6, 18.6.7, 18.6.8, 18.6.9, 18.6.10, 19.6.1, 19.6.2,19.6.3, 19.6.4, 19.6.5, 19.6.6, 19.6.7, 19.6.8, 19.6.9, 19.6.10, 20.6.1,20.6.2, 20.6.3, 20.6.4, 20.6.5, 20.6.6, 20.6.7, 20.6.8, 20.6.9, 20.6.10,21.6.1, 21.6.2, 21.6.3, 21.6.4, 21.6.5, 21.6.6, 21.6.7, 21.6.8, 21.6.9,21.6.10, 22.6.1, 22.6.2, 22.6.3, 22.6.4, 22.6.5, 22.6.6, 22.6.7, 22.6.8,22.6.9, 22.6.10, 1.7.1, 1.7.2, 1.7.3, 1.7.4, 1.7.5, 1.7.6, 1.7.7, 1.7.8,1.7.9, 1.7.10, 2.7.1, 2.7.2, 2.7.3, 2.7.4, 2.7.5, 2.7.6, 2.7.7, 2.7.8,2.7.9, 2.7.10, 3.7.1, 3.7.2, 3.7.3, 3.7.4, 3.7.5, 3.7.6, 3.7.7, 3.7.8,3.7.9, 3.7.10, 4.7.1, 4.7.2, 4.7.3, 4.7.4, 4.7.5, 4.7.6, 4.7.7, 4.7.8,4.7.9, 4.7.10, 5.7.1, 5.7.2, 5.7.3, 5.7.4, 5.7.5, 5.7.6, 5.7.7, 5.7.8,5.7.9, 5.7.10, 6.7.1, 6.7.2, 6.7.3, 6.7.4, 6.7.5, 6.7.6, 6.7.7, 6.7.8,6.7.9, 6.7.10, 7.7.1, 7.7.2, 7.7.3, 7.7.4, 7.7.5, 7.7.6, 7.7.7, 7.7.8,7.7.9, 7.7.10, 8.7.1, 8.7.2, 8.7.3, 8.7.4, 8.7.5, 8.7.6, 8.7.7, 8.7.8,8.7.9, 8.7.10, 9.7.1, 9.7.2, 9.7.3, 9.7.4, 9.7.5, 9.7.6, 9.7.7, 9.7.8,9.7.9, 9.7.10, 10.7.1, 10.7.2, 10.7.3, 10.7.4, 10.7.5, 10.7.6, 10.7.7,10.7.8, 10.7.9, 10.7.10, 11.7.1, 11.7.2, 11.7.3, 11.7.4, 11.7.5, 11.7.6,11.7.7, 11.7.8, 11.7.9, 11.7.10, 12.7.1, 12.7.2, 12.7.3, 12.7.4, 12.7.5,12.7.6, 12.7.7, 12.7.8, 12.7.9, 12.7.10, 13.7.1, 13.7.2, 13.7.3, 13.7.4,13.7.5, 13.7.6, 13.7.7, 13.7.8, 13.7.9, 13.7.10, 14.7.1, 14.7.2, 14.7.3,14.7.4, 14.7.5, 14.7.6, 14.7.7, 14.7.8, 14.7.9, 14.7.10, 15.7.1, 15.7.2,15.7.3, 15.7.4, 15.7.5, 15.7.6, 15.7.7, 15.7.8, 15.7.9, 15.7.10, 16.7.1,16.7.2, 16.7.3, 16.7.4, 16.7.5, 16.7.6, 16.7.7, 16.7.8, 16.7.9, 16.7.10,17.7.1, 17.7.2, 17.7.3, 17.7.4, 17.7.5, 17.7.6, 17.7.7, 17.7.8, 17.7.9,17.7.10, 18.7.1, 18.7.2, 18.7.3, 18.7.4, 18.7.5, 18.7.6, 18.7.7, 18.7.8,18.7.9, 18.7.10, 19.7.1, 19.7.2, 19.7.3, 19.7.4, 19.7.5, 19.7.6, 19.7.7,19.7.8, 19.7.9, 19.7.10, 20.7.1, 20.7.2, 20.7.3, 20.7.4, 20.7.5, 20.7.6,20.7.7, 20.7.8, 20.7.9, 20.7.10, 21.7.1, 21.7.2, 21.7.3, 21.7.4; 21.7.5,21.7.6, 21.7.7, 21.7.8, 21.7.9, 21.7.10, 22.7.1, 22.7.2, 22.7.3, 22.7.4,22.7.5, 22.7.6, 22.7.7, 22.7.8, 22.7.9, 22.7.10, 1.8.1, 1.8.2, 1.8.3,1.8.4, 1.8.5, 1.8.6, 1.8.7, 1.8.8, 1.8.9, 1.8.10, 2.8.1, 2.8.2, 2.8.3,2.8.4, 2.8.5, 2.8.6, 2.8.7, 2.8.8, 2.8.9, 2.8.10, 3.8.1, 3.8.2, 3.8.3,3.8.4, 3.8.5, 3.8.6, 3.8.7, 3.8.8, 3.8.9, 3.8.10, 4.8.1, 4.8.2, 4.8.3,4.8.4, 4.8.5, 4.8.6, 4.8.7, 4.8.8, 4.8.9, 4.8.10, 5.8.1, 5.8.2, 5.8.3,5.8.4, 5.8.5, 5.8.6, 5.8.7, 5.8.8, 5.8.9, 5.8.10, 6.8.1, 6.8.2, 6.8.3,6.8.4, 6.8.5, 6.8.6, 6.8.7, 6.8.8, 6.8.9, 6.8.10, 7.8.1, 7.8.2, 7.8.3,7.8.4, 7.8.5, 7.8.6, 7.8.7, 7.8.8, 7.8.9, 7.8.10, 8.8.1, 8.8.2, 8.8.3,8.8.4, 8.8.5, 8.8.6, 8.8.7, 8.8.8, 8.8.9, 8.8.10, 9.8.1, 9.8.2, 9.8.3,9.8.4, 9.8.5, 9.8.6, 9.8.7, 9.8.8, 9.8.9, 9.8.10, 10.8.1, 10.8.2,10.8.3, 10.8.4, 10.8.5, 10.8.6, 10.8.7, 10.8.8, 10.8.9, 10.8.10, 11.8.1,11.8.2, 11.8.3, 11.8.4, 11.8.5, 11.8.6, 11.8.7, 11.8.8, 11.8.9, 11.8.10,12.8.1, 12.8.2, 12.8.3, 12.8.4, 12.8.5, 12.8.6, 12.8.7, 12.8.8, 12.8.9,12.8.10, 13.8.1, 13.8.2, 13.8.3, 13.8.4, 13.8.5, 13.8.6, 13.8.7, 13.8.8,13.8.9, 13.8.10, 14.8.1, 14.8.2, 14.8.3, 14.8.4, 14.8.5, 14.8.6, 14.8.7,14.8.8, 14.8.9, 14.8.10, 15.8.1, 15.8.2, 15.8.3, 15.8.4, 15.8.5, 15.8.6,15.8.7, 15.8.8, 15.8.9, 15.8.10, 16.8.1, 16.8.2, 16.8.3, 16.8.4, 16.8.5,16.8.6, 16.8.7, 16.8.8, 16.8.9, 16.8.10, 17.8.1, 17.8.2, 17.8.3, 17.8.4,17.8.5, 17.8.6, 17.8.7, 17.8.8, 17.8.9, 17.8.10, 18.8.1, 18.8.2, 18.8.3,18.8.4, 18.8.5, 18.8.6, 18.8.7, 18.8.8, 18.8.9, 18.8.10, 19.8.1, 19.8.2,19.8.3, 19.8.4, 19.8.5, 19.8.6, 19.8.7, 19.8.8, 19.8.9, 19.8.10, 20.8.1,20.8.2, 20.8.3, 20.8.4, 20.8.5, 20.8.6, 20.8.7, 20.8.8, 20.8.9, 20.8.10,21.8.1, 21.8.2, 21.8.3, 21.8.4, 21.8.5, 21.8.6, 21.8.7, 21.8.8, 21.8.9,21.8.10, 22.8.1, 22.8.2, 22.8.3, 22.8.4, 22.8.5, 22.8.6, 22.8.7, 22.8.8,22.8.9 and 22.8.10.

Identification of Active Precursors. It is desirable to select the aminoacid residue or sequence of the invention compounds having one or morepeptide bonds, such as formula VII compounds, based on the substratespecificity of esterases and/or carboxypeptidases expected to be foundwithin cells where precursor hydrolysis is desired. To the extent thatthe specificity of these enzymes is unknown, one will screen a pluralityof nucleotide analogs or esters until the desired substrate specificityis found. This will be apparent from assay either of the generation offree phosphonate or of antimicrobial activity. One selects compoundsthat are (i) not hydrolyzed or hydrolyzed comparatively slowly in theupper gut, (ii) gut and cell permeable and (iii) hydrolyzed in the cellcytoplasm and/or systemic circulation. Screens with cells fromparticular tissues are used to identify precursors that are released inorgans susceptible to a target viral or microbial infection, e.g. in thecase of liver, precursor drugs capable of hydrolysis in the liver. Otherinfections, e.g. CMV or HIV, are treated with a precursor that ishydrolyzed at substantially the same rate and to substantially the samedegree in all tissues, with no one tissue preferentially hydrolyzing theprecursor nucleosides.

The assays used can be those known in the art including intestinal lumenstability, cell permeation, liver homogenate stability and plasmastability assays. These assays are used to determine the bioavailabilitycharacteristics of particular active precursors according to routinelyused methods.

Therapeutic Indications. The hydrolysis products of the inventioncompounds have activity against viruses, malignant cells and/orparasitic protozoans. For example,9-(3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and(2-phosphonylmethoxy)ethyl (PME) analogs of purine (adenine (A), guanine(G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (Hx)and pyrimidine (cytosine (C), uracil (U), thymine (T) were evaluated forantiviral properties. (S)-HPMPA; (S)-cyclic HTMPA, (S)-HPMPC, (S)-HFMPG,(S)-HPMPDAP, PMEDAP, PMEG and PMEA were active against herpes simplexvirus, type-1 and 2 (HSV-1 and -2). (S)-HPMPA and (S)-cyclic HMPA wereactive against varicella zoster virus (VZV). (S)-HPMPC was activeagainst human cytomegalovirus (HCMV). (S)-HPMPA and (S)-cyclic HPMPAwere shown to be active against adenovirus and vaccinia virus. PMEA,PMEDAP, and PMEMAP are active against human immunodeficiency virus(HIV).

Acyclic nucleotide analogs having a common PME side chain covalentlylinked to a purine or pyrimidine heterocyclic base were prepared andtested for in vivo antiviral activity against retroviruses and herpesviruses. The adenine analog, PMEA, was active in vitro against HIV andRauscher murine leukemia virus (R-MuLV), and was more potent in vivothan 3′-azido-3′-deoxythymidine (AZT) in the treatment of R-MuLV inmice. PMEA also had a significant antiviral effect in vivo againstmurine cytomegalovirus (MCMV), and jia vitro activity against HCMV. Theguanine analog, PMEG, was active in vitro against herpes viruses. Invivo PMEG was >50-fold more potent than acyclovir against HSV 1infection in mice.

(S)-HPMPA has potent and selective activity against a broad-spectrum ofDNA viruses, including HSV-1 and 2, VZV, thymidine kinasedefident (TK⁻)mutants of herpes simplex virus, HCMV, phocid herpesvirus type 1 (sealherpesvirus, SeHV), simian herpesvirus type 1 (SHV-1), or pseudorabiesvirus or Aujeszky's disease virus), bovid herpesvirus type 1 (infectiousbovine rhinotracheitis virus, BHV-1), equid herpesvirus type 1 (equineabortion virus, EHV-1), African swine fever (ASF) virus, vaccinia virus;and human adenoviruses, and retroviruses such as murine sarcoma virus(MSV). It is also reported that, in mice and rabbits in vivo thecompound is effective against both local and systemic infections withherpes simplex virus type 1, including herpetic keratitis caused by aTK⁻ mutant which is resistant to the classical antiherpes drugs(DeClercq, E., et al, Antiviral Res (1987) E:261-272; DeClercq, E., etal, Nature (1986) 323:464-467; Gil-Fernandez, C., et al, Antiviral Res(1987) 7:151-160; Baba, M., et al, Antimicrob Agents Chemother (1987)31:337-339).

Phosphonylmethoxyalkylpurine analogs have also been evaluated for theirantitumor activity in murine tumor models. HTMPA, PMEA, and PMEG werefound to be active against intraperitoneal P388 leukemia. PMEG was alsofound to be active against B16 melanoma.

As indicated above, the compounds of the invention are useful fortreatment of microbial infections, for treatment of tumors or for otherindications described below. Microbial infections include infection byviruses, parasites, yeasts and fungi. Exemplary viral infections thatmay be treated include infections mediated by DNA or RNA virusesincluding herpesviruses (CMV, HSV 1, HSV 2, EBV, varicella zoster virus, bovid herpesvirus type 1, equid herpesvirus type 1), papillomaviruses(HPV types 1-55), flaviviruses (including African swine fever virus andJapanese encephalitis virus), togaviruses (including Venezuelan equineencephalomyelitis virus), influenza viruses (types A-C), retroviruses(HIV 1, HIV 2, HTLV I, HTLV II, SIV, HBV, FeLV, FIV, MoMSV),adenoviruses (types 1-8), poxviruses (vaccinia virus), enteroviruses(polio virus type 1-3, hepatitis A virus), gastroenteritis viruses(Norwalk viruses, rotaviruses), hantaviruses (Hantaan virus),papovaviruses, rhinoviruses, parainfluinza virus types 1-4, rabiesvirus, and the like.

Some of the phosphonate compounds (such as PMEA) have a broad spectrumof antimicrobial activity and are thus unusual antiviral orantiparasitic agents. The activity of individual nucleotide analogs andnucleotide analog amidates is determined by routine assay of antiviral(or other antimicrobial) activity using enzyme inhibition assays, tissueculture assays, animal model assays and/or other acceptable assays.

Nucleotide analogs (phosphonates such as HPMPC, PMEA, etc) are believedto exert their antimicrobial activity, at least in part, by a two stepenzyme-mediated conversion to a diphosphate, followed by incorporationof the diphosphorylated nucleotide analog into nucleic acids. Theincorporation of the diphosphates into nucleic acid is mediated by viralor other microbial DNA or RNA polymerases (bacterial, retroviral, etc).Thus, nucleotide analogs (when diphosphorylated) are useful as chainterminators for dideoxynucleotide-type DNA sequencing protocols,provided that the nucleotide analog lacks a free hydroxyl group suitablefor polymerase mediated chain elongation. These compounds will not havea hydroxyl group at R²⁷ in compounds of formulas IV and VI or areacyclic. Nucleotide analogs of formula XV,(HO)₂P(O)—O—P(O)(OH)—O—(HO)P(O)-Z-B, can be prepared (Otvos, et al, NuclAcids Res (1987) 15:1763-1777) and provided in a kit with other reagents(such as klenow polymerase or T4 polymerase, dNTPs, etc) needed for DNAsequencing. The invention nucleotide analogs and nucleotide analogamidates can also be (1) applied to tissue culture systems to eliminateor reduce viral spread or growth during the production ofbiopharmaceuticals or other products (such as proteins or vaccines), (2)used to eliminate or reduce viral spread or growth in clinical samples(such as blood), and (3) used to stop growth of tissue culture orbacterial cells (using toxic amounts of compound) without interferingwith protein production.

Infections mediated by protozoan parasites can be treated using thecompounds of the invention. Such infections can also be treated usingthe corresponding nucleotide analogs of the invention nucleotide analogamidates. The term protozoa is intended to include those members of thesubphyla Sarcomastigophora and Sporozoa of the phylum Protozoa. Moreparticularly, the term protozoa as used herein is intended to includethose 30 genera of parasitic protozoa which are important to man becausethey either cause disease in man or in his domestic animals. Thesegenera are for the most part found classified in the superclassMastighphora of the subphylum Sarcomastigophora and the class Telosporeaof the subphylum Sporozoa in the classification according to Baker(1969). Illustrative genera of these parasitic protozoa includeHistomonas, Pneumocystis, Trypanosoma, Giardia, Trichomonas, Eimeria,Isopora, Leishmania, Entamoeba, Toxoplasma and Plasmodium. Parasiticprotozoans include Plasmodium falciparum, Plasmodium berghei, Plasmodiummalariae, Plasmodium vivax, Leishmania braziliensis, Leishmaniadonovani, Trypanosoma cruzi, Typanosoma brucei, Trypanosoma rhodesiense,Pneumocystis carinii, Entamoeba histolytica, Trichomonas vaginalis andthe like (de Vries, E., et al, Mol Biochem Parasitol (1991) 47:43-50).Nucleoside analog amidates of the invention and/or their correspondingnucleotide analogs can also be used to treat yeast or fungal infectionscaused by Candida glabrata, Candida tropicalis, Candida albicans, andother Candida species Cryptococcus species including Cryptococcusneoformans, Blastomyces species including Blastomyces dermatidis,Torulopsis species including Torulopsis glabrata, Coccidioides speciesincluding Coccidioides immitis, Aspergillus species and the like.

Pharmaceutical formulations. Compounds of the invention and theirphysiologically acceptable salts (hereafter collectively referred to asthe active ingredients) may be administered by any route appropriate tothe condition to be treated, suitable routes including oral, rectal,nasal, topical (including ocular, buccal and sublingual), vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural). The preferred route ofadministration may vary with for example the condition of the recipient.

While it is possible for the active ingredients to be administered aloneit is preferably to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the presentinvention comprise at least one active ingredient, as above defined,together with one or more acceptable carriers therefor and optionallyother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural) administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient with the carrier which constitutes oneor more accessory ingredients. In general the formulations are preparedby uniformly and intimately bringing into association the activeingredient with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as solution or a suspension in an aqueous liquid ora non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the active,ingredient therein.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, imannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the present invention include Tween® 60, Span® 80, cetostearylalcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate andsodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus the cream should preferably be anon-greasy, non-staining and washable product with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last-three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for nasal administration wherein the carrier is asolid include a coarse powder having a particle size for example in therange 20 to 500 microns (including particle sizes in a range between 20and 500 microns in increments of 5 microns such as 30 microns, 35microns, etc), which is administered in the manner in which snuff istaken, i.e. by rapid inhalation through the nasal passage from acontainer of the powder held close up to the nose. Suitable formulationswherein the carrier is a liquid, for administration as for example anasal spray or as nasal drops, include aqueous or oily solutions of theactive ingredient. Formulations suitable for aerosol administration maybe prepared according to conventional methods and may be delivered withother therapeutic agents such as pentamidine for treatment ofpneumocystis pneumonia.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The present invention further provides veterinary compositionscomprising at least one active ingredient as above defined together witha veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can be used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient can be controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given invention compound. Controlled releaseformulations adapted for oral administration in which discrete unitscomprising one or more compounds of the invention can be preparedaccording to conventional methods. Controlled release formulations maybe employed for the treatment or prophylaxis of various microbialinfections particularly human, bacterial, human parasitic protozoan orhuman viral infections caused by microbial species including Plasmodium,Pneumocystis, herpesviruses (CMV, HSV 1, HSV 2, VZV, and the like),retroviruses, adenoviruses and the like. The controlled releaseformulations can be used to treat HIV infections and related conditionssuch as tuberculosis, malaria, pneumocystis pneumonia, CMV retinitis,AIDS, AIDS-related complex (ARC) and progressive generalizedlymphadeopathy (PGL), and AIDS-related neurological concusions such asmultiple sclerosis, and tropical spastic paraparesis. Other humanretroviral infections that may be treated with the controlled releaseformulations according to the invention include Human T-cellLymphotropic virus (HTLV)-I and IV and HIV-2 infections.

The invention accordingly provides pharmaceutical formulations for usein the treatment or prophylaxis of the above-mentioned human orvetrinary conditions and microbial infections.

Therapeutic Administration. For each of the above-indicated utilitiesand indications the amount required of an active ingredient (as abovedefined) will depend upon a number of factors including the severity ofthe condition to be treated and the identity of the recipient and willultimately be at the discretion of the attendant physician orveterinarian. In general however, for each of these utilities andindications, a suitable, effective dose will be in the range 0.1 to 250mg per kilogram bodyweight of recipient per dose (including activeingredient(s) in a range between 0.1 mg and 250 mg/Kg/dose in incrementsof 0.5 mg/Kg/dose such as 2.5 mg/Kg/dose, 3.0 mg/Kg/dose, 3.5mg/Kg/dose, etc), preferably in the range 0.5 to 50 mg per kilogram bodyweight per dose and most preferably in the range 1 to 15 mg per kilogrambody weight per dose; an optimum dose is about 3.0 mg per kilogram bodyweight per dose. (Unless otherwise indicated all weights of activeingredient are calculated as the parent compound of formula I: for saltsthereof the figures would be increased proportionately). The desireddose is preferably presented as one dose or two sub-doses administeredat appropriate intervals throughout a period of one to seven days. It ispreferred to administer a dose once every 2, 3, 4, 5 or 6 days. Thedoses may be administered in unit dosage forms. The desired dose is maybe presented as one, two, or three sub-doses administered at appropriateintervals throughout the one to seven day period. These sub-doses may beadministered in unit dosage form, for example, containing 10 to 1000 mg,and or 100 to 500 mg of active ingredient per unit dosage form. Theformulations should be desirably administered to achieve peak plasmaconcentrations of the active compound of from about 1 to about 100 μM,preferably about 2 to 50 μM, most preferably about 3 to about 30 μM.

Compounds such as those of structures XXXI, XXXII and XXXIII (definedbelow) will generally (1) have a higher oral bioavailability than thecorresponding uncyclized nucleotide analog (e.g., cHPMPC compared toHPMPC) and/or (2) will exibit reduced toxicity when compared with thesame dose of the corresponding uncyclized nucleotide analog, and/or (3)will have greater efficacy when compared with the same dose of thecorresponding uncyclized nucleotide analog.

The compounds of the invention may be employed in combination with othertherapeutic agents for the treatment or prophylaxis of the infections orconditions indicated above. Examples of such further therapeutic agentsinclude agents that are effective for the treatment or prophylaxis ofviral, parasitic or bacterial infections or associated conditions or fortreatment of tumors or related conditions include3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′-deoxy-3′-thiacytidine(3TC), 2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A),2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), carbovir (carbocyclic2′,3′-dideoxy-2′,3′-didehydroguanosine), 3′-azido-2′,3′-dideoxyuridine,5-fluorothymidine, (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU),2-chlorodeoxyadenosine, 2-deoxycoformycin, 5-fluorouracil,5-fluorouridine, 5-fluoro-2′-deoxyuridine,5-trifluoromethyl-2′-deoxyuridine, 6-azauridine, 5-fluoroorotic acid,methotrexate, triacetyluridine,1-(2′-deoxy-2′-fluoro-1-β-arabinosyl)-5-iodocytidine (FIAC),tetrahydro-imidazo(4,5,1-jk)-(1,4)-benzodiazepin-2(1H)-thione (TIBO),2′-nor-cyclicGMP, 6-methoxypurine arabin oside (ara-M), 6-methoxypurinearabinoside 2′-O-valerate, cytosine arabinoside (ara-C),2′,3′-dideoxynucleosides such as 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxyadenosine (ddA) and 2′,3′-dideoxyinosine (ddI), acyclicnucleosides such as acyclovir, penciclovir, famciclovir, ganciclovir,HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA, HPMPDAP, (2R,5R)-9-[tetrahydro-5-(phosphonomethoxy)-2-furanyl]adenine, (2R,5R)-1-[tetrahydro-5-(phosphonomethoxy)-2-furanyl]thymine, otherantivirals including ribavirin (adenine arabinoside),2-thio-6-azauridine, tubercidin, ; aurintricarboxylic acid,3-deazaneoplanocin, neoplanocin, rimantidine, adamantine, and foscarnet(trisodium phosphonoformate), antibacterial agents includingbactericidal fluoroquinolones (ciprofloxacin, pefloxacin and the like),aminoglycoside bactericidal antibiotics (streptomycin, gentamicin,amicacin and the like) β-lactamase inhibitors (cephalosporins,penicillins and the like), other antibacterials including tetracycline,isoniazid, rifampin, cefoperazone, claithrimycin and azithromycin,antiparasite or antifungal agents including pentamidine(1,5-bis(4′-aminophenoxy)pentane), 9-deazainosine, sulfamethoxazole,sulfadiazine, quinapyramine, quinine, fluconazole, ketoconazole,itraconazole, Amphotericin B, 5-fluorocytosine, clotrimazole,hexadecylphosphocholine and nystatin, renal excretion inhibitors such asprobenicid, nucleoside transport inhibitors such as dipyridamole,dilazep and nitrobenzylthioinosine, immunomodulators such as FK506,cyclosporin A, thymosin α-1, cytokines including TNF and TGF-β,interferons including IFN-α, IFN-β and IFN-γ, interleukins includinginterleukin I, II, III, IV, V, VI, VII, VIII, X, XII, XIIImacrophage/granulocyte colony stimulating factors including GM-CSF,G-CSF, M-CSF, cytokine antagonists including anti-TNF antibodies,anti-interleukin antibodies, soluble interleukin receptors, proteinkinase C inhibitors and the like.

Immunogens and Antibodies. The compounds of this invention, or thebiologically active substances produced from these compounds byhydrolysis in vivo, are used as immunogens to prepare antibodies capableof binding specifically to the compounds or their hydrolysis products.The immunogenic compositions therefore are useful as intermediates inthe preparation of antibodies for use in diagnostic or quality controlassays for the compounds or their hydrolysis products. The antibodiesare useful for measuring the presence, absence or amounts of thecompounds by any convenient homogenous or heterogenous procedure such asfluorescence polarization immunoassay, fluorescence immunoassay (usingfluorescent labels such as fluorescein and the like), radioimmunoassay,enzyme immunoassay (using enzyme indicators such as alkalinephosphatase, horseradish peroxidase, glucose oxidase, urease and thelike) and nephelometric inhibition assay by described methods (WO92/22639, incorporated herein by reference). Such assays usually requirea tracer (such as a fluorescent or radiolabeled labeled inventioncompound), an antibody and the sample to be analyzed containing thecompound.

The hydrolysis products of interest are the phosphonates resulting fromthe hydrolysis of the amidate or ester bond(s) of the precursorcompounds of this invention, for example HPMPC, 6-aza-HPMPC, cyclicHPMPC, PMEA, PMEG, PMPDAP, PMPA, D4TMPI, D4AMPI, cyclic HPMPA, FPMPA,PMEDAP, PMEMAP, 7-deaza-8-aza-FPMPA, 7-deaza-8-aza-HPMPA, cyclic7-deaza-8-aza-HPMPA, 7-deaza-8-aza-PMPA, 8-aza-F?MPA, 8-aza-HPMPA,cyclic 8-aza-HPMPA, 8-aza-PMPA, PMPG, PMPMAP, 1-deaza-HPMPA, cyclic1-deaza-HPMPA, 1-deaza-PMPA, 1-deaza-PMPG, 1-deaza-PMPMAP,1-deaza-PMPDAP, 3-deaza-HPMPA, cyclic 3-deaza-HPMPA or 3-deaza-PMPA.Thus, the antibodies of this invention will be capable of binding to theprecursors without binding to the hydrolysis products, will be capableof binding to the hydrolysis products without binding to the precursors,or will be capable of binding specifically to both. The antibodies willnot cross-react with naturally-occurring nucleotides or nucleosides.

The immunogens of this invention contain the precursor or hydrolyticproducts in association with an immunogenic substance such as a proteinor peptide. Immunogenic substances include adjuvants such as Freund'sadjuvant, immunogenic proteins such as viral, bacterial, yeast, plantand animal polypeptides, in particular keyhole limpet hemocyanin, serumalbumin, bovine thyroglobulin or soybean trypsin inhibitor, andimmunogenic polysaccharides. Typically, the precursor or a compoundhaving the structure of a precursor hydrolytic product is covalentlyconjugated to an immunogenic polypeptide or polysaccharide by the use ofa polyfunctional (ordinarily bifunctional) cross-linking agent. Methodsfor the manufacture hapten immunogens are conventional per se and any ofthe methods used heretofore for conjugating haptens to immunogenicpolypeptides or the like are suitably employed here as well, taking intoaccount the functional groups on the precursors or hydrolytic productswhich are available for cross-linking.

Typically the polypeptide is conjugated to a site on the heterocyclicbase functionality of the compound or hydrolysis product rather than toa site on the alkyl or substituted-alkyl phosphonate moiety. In general,the site will be an amino group located on the purine or pyrimidinemoiety of the nucleoside phosphonate, at the 5 position of pyrimidines(such as cytosine or uracil), at the 1 position of purines (such asadenosine or guanine) or, for compounds having a cyclic structurecorresponding to a sugar or sugar analog and having a free hydroxylgroup, through the hydroxyl group (usually at the 3′ or 2′ positions).Alternatively, the precursor compound is cross-linked through thephosphonate, typically by amidation or esterification of the phosphonateby the polypeptide itself or by a cross-linking functionality covalentlybonded to the polypeptide. Thus, the groups L¹ or L² in structures(L¹)(L²)-P(O)-Z-B can be immunogenic proteins (having more than 50 aminoacid residues, usually less than 1000 residues) or peptides (about 5 to50 amino acid residues).

The conjugates are prepared in conventional fashion. For example,N-hydroxysuccinimide, succinic anhydride or alkN═C═Nalk are useful inpreparing the conjugates of this invention. The conjugates contain aprecursor, its hydrolysis product, or both. Ordinarily, the conjugateswill comprise the hydrolysis product, i.e., the biologically activedrug. The conjugates are separated from starting materials andbyproducts using chromatography or the like, and then are sterilefiltered and vialed for storage.

Animals are typically immunized against the immunogenic conjugates orderivatives by combining 1 mg or 1 μg of conjugate (for rabbits or mice,respectively) with 3 volumes of Freund's complete adjuvant and injectingthe solution intradermaily at multiple sites. One month later theanimals are boosted with ⅕ to 1/10 the original amount of conjugate inFreund's complete adjuvant (or other suitable adjuvant) by subcutaneousinjection at multiple sites. 7 to 14 days later animals are bled andthe-serum is assayed for the desired antibody titer. Animals are boosteduntil the titer plateaus. Preferably, the animal is boosted with theconjugate in which the precursor or product is linked to a differentprotein, through a different cross-linking agent or both. Optionally,aggregating agents such as alum are used to enhance the immune response.

After immunization, monoclonal antibodies are prepared by recoveringimmune lymphoid cells (typically spleen cells or lymphocytes from lymphnode tissue) from immunized animals and immortalizing the cells inconventional fashion, e.g., by fusion with myeloma cells or byEpstein-Barr virus transformation and screening for dones expressing thedesired antibody. The hybridoma technique described originally be Kohlerand Milstein, Eur. J. Immunol. (1976) 6:511 has been widely applied toproduce hybrid cell lines that secrete high levels of monoclonalantibodies against many specific antigens.

It is possible to fuse cells of one species with another. However, it ispreferably that the source of the irmmunized antibody producing cellsand the myeloma be from the same species.

The hybrid cell lines are maintained in culture in vitro. The cell linesof this invention are selected or maintained in ahypoxanthine-aminopterin thyridine (HAT) medium. However, theestablished hybridoma cell line can be maintained on a variety ofnutritionally adequate media. The secreted antibody is recovered fromculture by conventional methods such as precipitation, ion exchangechromatography, affinity chromatography, or the like. The antibodiesdescribed herein are also recovered from hybridoma cell cultures byconventional methods for purification of IgG or IgM as the case may bethat heretofore have been used to purify immunoglobulins from pooledplasma, e.g., ethanol or polyethylene glycol precipitation procedures.The purified antibodies are sterile filtered, and optionally areconjugated to a detectable marker such as an enzyme or spin label foruse in diagnostic assays of test samples.

The antibodies of this invention are obtained from any animal species,but ordinarily are murine or rat. Once a monoclonal antibody having thedesired specificity and affinity is obtained, other conventionalmodifications of the antibodies are within the scope of this invention.For example, the complementarity determining regions of an animalantibody, together with as much of the framework domain as is needed,are substituted into an antibody of another animal species or class toproduce a cross-class or cross-species chimeric antibody. Fragments orother amino acid sequence variants of monoclonal antibodies also areencompassed within the meaning of antibody as that term is used herein,for example, Fab, Fab′ or (Fab′)2 fragments, single chain antibodies, bior polyspecific antibodies, and the like.

The antibodies of this invention are from any suitable class or isotype,e.g. IgG, IgM, IgA, IgD or IgE. They may or may not participate incomplement binding or ADCC. Typically, hybridomas which are capable ofbinding to the immunogen are screened for the ability to bind to thehapten itself in typical test samples (plasma, serum and the like) withthe requisite degree of affinity. The desired affinity will depend uponthe use intended for the antibody, but should be adequate to function ina conventional competitive-type ELISA or radioimmunoassays, or inconventional EMIT immunoassays.

The antibodies of this invention are used in such assays together with alabeled from of the precursor or its hydrolytic product. Alternatively,the antibody is labeled. Suitable labels are well-known and includeradioisotopes, enzymes, stable free radicals, fluorophors,chemiluminescent moieties and other detectable groups heretoforeemployed to prepare covalent conjugates for use in assays. Methods forlinking the labels to ligand amino groups, or amino acid side chains ortermini of polypeptides, are known and are suitable for use herein.Other suitable linking methods will be apparent to the ordinary artisan.

The antibodies and labeled ligands herein optionally are assembled intokits for use in therapeutic drug monitoring or evaluation, or forprocess quality control, and used in the conventional manner.

Diagnostic applications. Novel compounds described herein are useful asintermediates in the preparation of detectable labels foroligonucleotide probes. The compounds are hydrolyzed to the diacid,diphosphorylated and then incorporated into an oligonucleotide byconventional enzymatic or chemical means. The incorporated heterocyclicbase from the invention will generally be capable of participating inheterocyclic base pairing and thus will not interfere substantially withthe binding of the oligonucleotide to its complementary sequence (E.DeClerq (1993) 3:85-96); should it interfere with oligonucleotidebinding to its complementary sequence, the nucleotide analog isincorporated as the final 3′ terminal residue, an innocuous position anda conventional site for oligonucleotide labeling. The nucleotide analogcompound in the oligonucleotide is detected by any means, such as NMR,immune, fluorescence or radiolabel detection.

Bis amidate synthesis. Synthesis of bis-phosphoroamidate nucleotideanalogs of Formula Id,

where L¹ and L² are the same and are an amino acid, dipeptide,tripeptide or oligopeptide (4, 5 or 6 amino acid residues) are preparedby conversion of a nucleotide analog (such as PMEA, HPMPC, HPMPA, PMEG,FPMPA, PMTDAP,9-[2,3-dideoxy-2,3-didehydro4-phosphonomethoxy-β-D-erythrofuranosyl]adenine(D4AMPI; reg no. 132178-53-1),1-[2,3-dideoxy-2,3-didehydro-4-phosphonomethoxy-β-D-erythrofuranosyl]thymine(D4TMPI; reg no. 132178-49-5) and the like) directly to thecorresponding bis-phosphoroamidate compound. L¹ is a protein, an aminoacid, dipeptide, tripeptide or oligopeptide (4 to 6 amino acid residues)which is esterified at free α-carboxyl group(s) by R⁴. Suitable R⁴groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl,benzyl, N-ethylmorpholino, pivaloyloxyrnethyl and the like. The aminoacids can comprise an aliphatic or aromatic side group (such as ala,phe, pro, leu, ile, met, trp and the like) or a dipeptide comprisingamino acids having aliphatic or aromatic side groups (such as gly-gly,ala-ala, gly-ala, ala-gly, phe-gly, gly-phe, ala-phe, phe-ala, leu-ala,ala-leu and the like), or is a tripeptide comprising amino acids havingaliphatic or aromatic side groups or is an oligopeptide comprising aminoacids having aliphatic or aromatic side groups.

The procedure is suitable for all of the nucleotide analogs describedherein. The synthesis is accomplished by suspension of the nucleotideanalog and approxirmately 2 equivalents of the L¹ species in a solventsuch as dry pyridine or DMF (dimethylformamide) optionally containing anon-nucleophilic organic base such as triethylamine (about 3 to 10equivalents). The dehydration step is accomplished by modification of adescribed reaction (Mukaiyama, T. et al, J Am Chem Soc (1972)94:8528-8532) by adding a 1:1 mixture of triphenylphosphine (reg. no.603-35-0; Aldrich) and 2,2′-dipyridyl disulfide (2 to 4 equivalents;reg. no. 2127-03-9; Aldrich) in pyridine to the nucleotide analog/aminoacid mixture and (a) stirring at room temperature for about 4 to 16hours or (b) heating to 60° C. to 100° C. (including any temperature inone degree C. increments between 60° and 100° C. such as 70°, 80° or 90°C.) for about 4 to 16 hours. The resulting reaction mixture is thenconcentrated and the final bis-amidate product is recovered and purifiedby conventional methods.

An alternative reaction suitable for synthesizing most amidate compoundsis converting a nucleotide analog phosphonate to the correspondingchloridate by reaction with thionyl chloride in solvent (DMF) asdescribed in EP 481 214. An amino acid, dipeptide or other moleculebearing a free amine is then reacted with the chioridate to yield thecorresponding bis-amidate.

Synthesis of compounds of Formula Id having amino acids that containamino, guanidino or carboxyl groups (such as lys, arg, his, asn, gln,lys-lys, arg-arg, lys-arg and the like) is accomplished by the samemethod, but using protected amine or carboxyl groups. After synthesis ofthe protected bis-amidate compound, the protecting groups are removed byconventional methods. Suitable protecting groups are well known andinclude acid labile groups such as p-tosyl, BOC (t-butoxycarbonyl) andFMOC (fluorene methoxycarbonyl) for protecting amine groups. Groups suchas t-butyl, methyl, ethyl, benzyl and the like can be used to protectcarboxyl groups. These groups can be removed under acid, base orhydrogenolysis conditions or can be removed with an esterase accordingto conventional methods.

Synthesis of compounds of Formula Id having amino acids such as tyr,cys, ser and thr is accomplished by optionally protecting hydroxyl orthiol groups using protecting groups know in the art. For example, thehydroxyl group of ser, thr or tyr can be protected using benzyl, ethyland the like and the thiol group of cys can be protected using trityl,p-methylbenzyl and the like. The choice of a protecting group willdepend on the stability of the bis-amidate toward conditions used toremove a particular protecting group. Appropriate protecting groups canbe selected or determined-by the skilled artisan using routine methods.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., Pharm Res (1992) 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of-bis amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in bis amidate compounds. Amino acids in the D configurationcan be used to reduce the susceptibility of a di- or tripeptide tohydrolysis by proteases common to the brush border such asaminopeptidase N (EC 3.4.11.2). In addition, di- or tripeptides withamino acid residues can be selected on the basis of their relativeresistance to hydrolysis by proteases found in the lumen of theintestine. For example, tripeptides or oligopeptides lacking asp and/orglu are poor substrates for aminopeptidase A (EC 3.4.11.7) and di- ortripeptides lacking amino acid residues on the N-terminal side ofhydrophobic amino acids (leu, tyr, phe, val, trp) are poor substratesfor endopeptidase 24.11 (EC 3.4.24.11) while peptides lacking a proresidue at the penultimate position at a free carboxyl terminus are poorsubstrates for carboxypeptidase P (EC 3.4.17). Similar considerationscan also be applied to the selection of peptides that are eitherrelatively resistant or relatively susceptible to hydrolysis bycytosolic, renal, hepatic, serum or other peptidases.

Synthesis of N-alkylamine amidates (where —NHR⁴⁰ is linked to thephosphorus atom and R⁴⁰ is C₁₋₂₀ alkyl, including C₄₋₁₆ alkyl) isaccomplished essentially as described (Saito Chem. Pharm. Bull. (1991)39:3207). Thus, compounds such as, for example, of structure(R⁴⁰HN)(L¹)P(O)-Z-B² or

wherein B² is B or B¹, are synthesized in this manner.

Amidate-ester synthesis. Synthesis of mixed amidate-ester nucleotideanalog amidates of Formula Id where L¹ is an amino acid ester and L² isa group of the formula OR, SR or OR³¹ is accomplished by conversion of anucleotide analog (such as PMEA, HPMPC, HPMPA, PMEG, FPMPA, PMPDAP,D4AMPI, D4TMPI and the like) di- or bis-ester to a corresponding mixedester-phosphoroamidate compound. A bis ester is converted to a monoester by treatment with a base such as ammonia to remove one estergroup. The resulting mono ester is then converted to a mixedamidateester as described for synthesis of bis amidate compounds.

Bis ester synthesis. Bis esters of the formula (RO)₂P(O)-Z-B aregenerally synthesized as described in EP 481 214 or as described inMukaiyama, T. et al, J Am Chem Soc (1972) 94:8528-8532. Dialkylphosphonate esters are synthesized via conversion of adichlorophosphonate (chioridate) such as (Cl)₂P(O)-Z-B (Quast, H. et al,Synthesis (1974) 7:489-490; Quast, H. et al, Synthesis (1974) 7:490;Moedritzer, K. et al, Synth Reac Inorg Met-Org Chem (1974) 5:417-27;Moedritzer, K., Chem Abs 82:86340; Stowell, M. H. B.; et al Tet Lett(1990) 31:3261-73262) to a corresponding dialkylester (or dialkylamide)by reaction with alcohols (or amines). Monoalkylesters (or monoalkylamides) are obtained by hydrolysis of the disubstituted phosphonatein base (NaOH, KOH and the like). Disubstituted diacyloxyalkylphosphonates are obtained by reaction of the unsubstituted phosphonatewith a substituted chloromethyl ester (R—C(O)O—O—CH(R)—Cl). Acorresponding monosubstituted acyloxyalkyl phosphonate is obtained byhydrolysis in acid or base.

For synthesis of Z substructures having a free hydroxyl group, such as(RO)₂P(O)—CH₂—O—CH(CH₂OH)CH₂—, the hydroxyl is, in some cases, protectedby a protecting group such as benzyl, acetyl, trityl, dimethoxytrityland the like.

Bis esters having aryl, substituted aryl, alkyl-aryl or substitutedalkyl-aryl (such as phenyl, alkoxyphenyl, benzyl, alkoxybenzyl) are alsosynthesized as described by reaction of (OH)₂P(O)-B-Z with thionylchloride and a catalytic amount of DMF in a solvent such asacetonitrile. The resulting dichloridate, P(O)(Cl)₂-Z-B is then reactedwith about 4, 5 or 6 equivalents of the sodium or potassiumn alkoxide ora sodium or potassium aryloxide obtained from reaction with sodiumhydride or potassium hydride and the alcohol (such as phenol, benzylalcohol and the like) in a solvent such as THF or acetonitrile at areduced temperature (below about −70° C., preferably about −76° C. to−78° C.).

cHPMPC and the cyclic analogues of other cHPMPs are prepared by a numberof methods from the free hydroxy phosphonic acid. These methods includetreatment with DCC in DMF, reaction with Vilsmeier's reagent(ClCH═N(CH₃)₂Cl), or methods of phosphate activation known per se. Inone embodiment of this invention for the preparation of a cHMP from thecorresponding phosphonate nucleotide analog, the phosphonate is (a)treated with CICH═N(CH₃)₂Cl to yield the phosphonylchloridate and (b)optionally the phosphonylchloridate is reacted with a nucleophine(preferably at low temperature, e.g. lower than about −20° C.) such asan alcohol or amine to produce one of the intermediates described above.In a further step the product of steps (a) or (b) are subject tohydrolysis or protonolysis (typically acid protonolysis) respectively toyield the cHSNA (treatment of the product of step (a)) or itsintermediate (treatment of the product of step (b)). Vilsmeier's reagentis advantageously produced in situ by combining SOCl₂, PCl₅, POCl₃,CCOCl₂ or the like with DMF. Advantageously, the product of step (a) isnot purified or separated from the reaction mixture before being reactedwith the nucleophile, a distinct economic advantage for this syntheticroute. The compounds of structure (Ia) and (Va) are readily made fromtheir uncyclized counterparts by the same methods, e.g. treatment withDCC in DMF.

Substituted and unsubstituted alkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl and other L¹ esters and amidates of cHPMPs typically aremade by reacting the appropriate HPMP compound with SOCl₂/DMF to yieldthe activated phosphonylchioride (see Scheme 1), followed by treatmentwith the corresponding nucleophile (e.g. alkoxide, phenolate, amine,etc.) to yield the protected intermediate formarnidine which issubsequently hydrolyzed to the target compound. Alternatively, esterscan also be prepared as depicted in Scheme 2. The N-,O-protectedintermediate phosphonate diester is obtained from the three buildingblocks by known methods. The N- and O-protecting groups are subsequentlyremoved followed by treatment of the phosphonate diester a with NaHleading to cyclization yielding target compound 4. A third method forthe synthesis of cHSNA esters entails alkylation of the cHSNA usingcommon alkylating agents D¹L (where L is a leaving group) such as alkylhalides, tosylates, diazoalkanes and the like (see Scheme 3). Thismethod is particularly useful for preparing acyloxyalkyl esters bytreatment of the cHSNA with the corresponding acyloxyalkylhalide. In anexemplary method for the preparation of acyloxyalkyl esters of cHPMPs,as shown in more detail in Example 12, DCC and R⁴⁵C(O)OCH₂Cl are reactedwith the cyclic compound; but in contradistinction with prior methodsthe stoichiometric proportion of DCC: R⁴⁵C(O)OCH₂Cl, cyclic HUMP is1-2:1-2:1. Use of such low proportions of reactants lessens sidereactions with any exocyclic amino group of B and thereby greatlyimproves yields. R⁴⁵ is H or is C₃-C₁₂ alkyl which is unsubstituted orsubstituted by substituents independently selected from the groupconsisting of OH, O, N and halogen, C₃-C₆ aryl which is unsubstituted orsubstituted by substituents independently selected from the groupconsisting of OH, O, N and halogen or C₃-C₉aryl-alkyl which isunsubstituted or substituted by substituents independently selected fromthe group consisting of OH, O, N and halogen

Each of the following schemes exemplify HPMPC as the nucleotide analog.However, any B is employed in place of cytosine, provided that anyexocyclic oxo or amino groups are protected as required. Also, step 3 ofscheme 1 will be omitted when B contains no exocyclic amine.

A third method for the synthesis of cyclic HPMP esters entailsalkylation of the cyclic HPMP ester as shown in Scheme 3 using commonalkylating agents R³⁵Lv (where Lv is a leaving group) such as alkylhalides, tosylates, diazoalkanes and the like. This method isparticularly useful for preparing acyloxyalkyl esters by treatment ofthe cyclic HPMP (cHPMP) with the corresponding acyloxyalkylhalide.

Compounds where Z is of structure V and R²⁵ and R²⁹ is oxygen aresynthesized by addition-elimination reaction using a compound ofstructure 50,

previously described for B=adenine (EP 398 231) with iodine (about 2equivalents) in organic solvent (such as acetonitrile or methylenechloride) at about 15-24° C. and a compound having the structure(R³⁵O)₂P(O)—CH₂—OH, wherein R³⁵ is R or R³¹ (defined below), to yieldthe 3-iodophosphonate diester of structure 51,

which is then eliminated to yield the corresponding structure V compoundby reaction with about 5 equivalents of a base such as sodium methoxideor DBU in anhydrous organic solvent such as methanol or tetrahydrofuranat room temperature for about 2-12 hours. The following schemes showsynthesis of intermediates having fluorine or iodine at the 3′ positionthat are converted to structure V compounds by elimination with a base.N-Fluorodibenzenesulfonamide is available commercially (Aldrich).Structure V compounds where B and the phosphbnate ester substituent atthe 4′ position are either both up or down (i.e., substituents at the 1′and 4′ positions are cis with respect to each other) are obtained byusing the corresponding structure 50 reactant as follows

When the reaction with iodine is conducted at high temperature (about50-80° C., usually about 60-70° C.), a scalemic intermediate results asfollows

intermediate is then converted to the corresponding structure V compoundand the various cis and trans isomers can be separated using standardmethods such as HPLC, RPLC or crystallization.

Exemplary esters are of the formula, (R³¹O)₂P(O)-Z-B, (RO)(R³¹O)P(O)-Z-Bor (RO)₂P(O)-Z-B, wherein R³¹ is independently2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester,—CH₂—C(O)—N(R⁷)₂ wherein each R⁷ is the same or different,—CH₂—S(O)(R⁷), —CH₂—S(O)₂(R⁷), —CH₂—CH(OC(O)CH₂R⁷)—CH₂(OC(O)CH₂R⁷),cholesteryl, a 5 or 6 carbon monosaccharide, disaccharide oroligosaccharide (3 to 9 monosaccharide residues), enolpyruvate(HOOC—C(═CH₂)O), glycerol, α-D-β-diglycerides (wherein the fatty acidscomposing glyceride lipids generally are naturally occurring saturatedor unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty acids such as linoleic,lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic andthe like fatty acids), trimethoxybenzyl, triethoxybenzyl, 2-alkylpyridinyl. (C₁₋₄ alkyl),

C₃-C₆ aryl (including phenyl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2-and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 2-, 3- and4-pyridinyl and 2-, 4- and 5-pytimidinyl) substituted by 3, 4 or 5halogen atoms or 1 or 2 atoms or groups selected from halogen, C₁-C₁₂alkoxy (including methoxy, ethoxy, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethoxy and 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxysubstituted phenyl), cyano, nitro, OH, C₁-C₁₂ haloalkyl (1 to 6 halogenatoms), C₁-C₁₂ alkyl (including methyl and ethyl), C₂-C₁₂ alkenyl orC₂-C₁₂ alkynyl; or R³¹ is C₁-C₄ alkylene-C₃-C₆ aryl (including benzyl,—CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl, —CH₂-oxazolyl,—CH₂-isoxazolyl, —CH₂-thiazolyl, —CH₂-isothiazolyl, —CH₂-pyrazolyl,—CH₂-pyridinyl and —CH₂-pyrimidinyl) substituted in the aryl moiety by 3to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen,C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁-C₁₂haloalkyl (1 to 6 halogen-atoms; including —CH₂—CCl₃), C₁-C₁₂ alkyl(including methyl and ethyl), C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl. Methodsfor linking cholesteryl, saccharide and other moieties to reactivegroups have been described (Hadfield Adv. Pharmacol. Chemother. (1984)20:21; Gouyette Tet. Lett. (1989) 30:6019; Ksander J. Med. Chem. (1994)37:1823).

The compounds are used as intermediates in the synthesis of mixedamidate-ester nucleotide analog amidates, or in some cases, as drugs perse. Additional exemplary ester compounds have the formulas(R³¹O)₂P(O)-Z¹-B or (RO)(R³¹O)P(O)-Z¹-B, where Z¹ is defined to mean thesubstructure in the following representative structures;(R³¹O)₂—P(O)—CH₂—O—CH₂—CH₂—B, (R³¹O)₂—P(O)—CH₂—O—C#H(CH₂OH)—CH₂—B,(R³¹O)₂—P(O)—CH₂—O—C#H(CH₃)—CH₂—B, (R³¹O)₂—P(O)—CH₂—O—C#H(CH₂F)—CH₂—B,(R³¹O)₂—P(O)—CH₂—O—C#H(CH═CH₂)—CH₂—B,(R³¹O)₂—P(O)—CH₂—O—C#H(CH₂N₃)—CH₂—B,

where C#, R²⁵-R²⁹, R³¹ and B have the meanings previously defined withthe proviso that PMEA bis(4-nitrobenzyl ester) and PMEAbis(4-trifluoromethyl ester) are excluded and for structure XXIX, R²⁹and R²⁵ are both O. Additional ester and nucleotide compounds are of theformula

where substituents linked to the carbon atom designated # are in the R,S or RS configuration and R³¹ and B are as previously defined.Nucleotides and esters of the formulas

wherein #, B, R²⁵, R²⁶ R²⁷, R²⁸, R²⁹, R³¹, R³³ and R³⁴ are as defined,R³⁵ is defined as R or R³¹ and for structure XXX, when R²⁹ is CH₂ or Oand R²⁵ is CH₂ or O, R³⁵ is not H or C₁-C₆ alkyl, are new. Compoundshaving R³⁵ include species where both R³⁵ are both H and their saltsincluding pharmaceutically acceptable salts.

Exemplary R³¹ include 2-, 3- and 4-alkoxyphenyl (C₁-C₁₂ alkyl including2-, 3- and 4-methoxyphenyl and 2-, 3- and 4-ethoxyphenyl), 2-, 3- and4-carboethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-0-acetylphenyl, 2-, 3- and4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-and 3,5-dihalophenyl (including 2,4-difluorophenyl and3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms,C₁-C₁₂ alkyl including 4-trifluoromethylphenyl), 2-, 3- and4-cyanophenyl, and 2-, 3- and 4-nitrophenyl, 2-, 3- and4-haloalkylbenzyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including4-trifluoromethylbenzyl), α-D-galactose, α-D-glucose, α-D-fructose. Thebis esters of formula (OR³¹)(OR³¹)P(O)-Z-B and (OR)(OR³¹)P(O)-Z-B arenovel and are useful as intermediates in the synthesis of the mixedamidate-ester nucleotide analog amidates of the invention. Thesecompounds can also be used directly as antimicrobial agents per se.Table 5 lists a group of exemplary bis esters of compounds having thestructure (OR³⁵)₂P(O)-Z-B which includes novel compounds of struture(OR³¹)₂P(O)-Z-B.

TABLE 5 OR³⁵* 1 —O—C₆H₄F 2 —O—C₆H₃F₂ 3 —O—C₆H₄—OCH₃ 4 —O—C₆H₃—(OCH₃)₂ 5—O—C₆H₄—OC₂H₅ 6 —O—C₆H₃—(OC₂H₅)₂ 7 —O—CH₂—C₆H₄F 8 —O—C₆H₄—(C(O)—O—C₂H₅)₂9 —O—C₆H₄—C(O)—O—C₂H₅ 10 —O—C₆H₃—(O—C(O)—CH₃)₂ 11 —O—C₆H₃—C(O)—O—C₃H₇ 12—O—CH₂—C₆H₄—O—CO—CH₃ 13 —O—C₅H₄N 14 —O—C₆H₃—(OC₂H₅)(OH) 15 —O—C₆H₅ 16—O—CH₂—O—C(O)—C(CH₃)₃ B 1 adenin-9-yl 2 guanin-9-yl 3 cytosin-1-yl 42,6-diaminopurin-9-yl 5 2-aminopurin-9-yl 6 thymidin-1-yl 75-fluorocytosin-1-yl —P(O)-Z-B** 1 —P(O)—CH₂—O—CH₂—CH₂—B 2—P(O)—CH₂—O—C^(#)H(CH₂—OR⁴)—CH₂—B 3 —P(O)—CH₂—O—C^(#)H(CH₃)—CH₂—B 4—P(O)—CH₂—O—C^(#)H(CH₂F)—CH₂—B 5 —P(O)—CH₂—O—C^(#)H(CH═CH₂)—CH₂—B 6—P(O)—CH₂—O—C^(#)H(CH₂N₃)—CH₂—B 7 ** 8 ** *Monosubstituted phenyl andbenzyl compounds (i.e., R³⁵ numbers 1, 3, 5, etc) include 2-, 3- and4-substituted compounds and disubstituted phenyl compounds (i.e., R³⁵numbers 2, 4, 6, etc) include 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-substituted compounds. **The structure ═P(O)— indicates that twobonds are occupied by OR³⁵; Z structure 7 is of formula IV where R²⁵ andR²⁹ are O, R²⁶ is S, R²⁷ is absent and R²⁸ is H and includes the (+) and(−) enantiomers; structure 8 is of formula V where R²⁵ and R²⁹ are O.

Compounds listed in Table 5 are designated herein by numbers assigned to(OR³⁵)₂ (where each R³⁵ is the same), Z and B according to the followingconvention, R³⁵.Z.B. Exemplary compounds include 1.1.1, 2.1.1, 3.1.1,4.1.1, 5.1.1, 6.1.1, 7.1.1, 8.1.1, 9.1.1, 10.1.1, 11.1.1, 12.1.1,13.1.1, 14.1.1, 15.1.1, 16.1.1, 1.2.1, 2.2.1, 3.2.1, 4.2.1, 5.2.1,6.2.1, 7.2.1, 8.2.1, 9.2.1, 10.2.1, 11.2.1, 12.2.1, 13.2.1, 14.2.1,15.2.1, 16.2.1, 1.3.1, 2.3.1,3.3.1, 4.3.1, 5.3.1, 6.3.1, 7.3.1, 8.3.1,9.3.1, 10.3.1, 11.3.1, 12.3.1, 13.3.1, 14.3.1, 15.3.1, 16.3.1, 1.4.1,2.4.1, 3.4.1, 4.4.1, 5.4.1, 6.4.1, 7.4.1, 8.4.1, 9.4.1, 10.4.1, 11.4.1,12.4.1, 13.4.1, 14.4.1, 15.4.1, 16.4.1, 1.5.1, 2.5.1, 3.5.1, 4.5.1,5.5.1, 6.5.1, 7.5.1, 8.5.1, 9.5.1, 10.5.1, 11.5.1, 12.5.1, 13.5.1,14.5.1, 15.5.1, 16.5.1, 1.6.1, 2.6.1, 3.6.1, 4.6.1, 5.6.1, 6.6.1, 7.6.1,8.6.1, 9.6.1, 10.6.1, 11.6.1, 12.6.1, 13.6.1, 14.6.1, 15.6.1, 16.6.1,1.7.1, 2.7.1, 3.7.1, 4.7.1, 5.7.1, 6.7.1, 7.7.1, 8.7.1, 9.7.1, 10.7.1,11.7.1, 12.7.1, 13.7.1, 14.7.1, 15.7.1, 16.7.1, 1.8.1, 2.8.1, 3.8.1,4.8.1, 5.8.1, 6.8.1, 7.8.1, 8.8.1, 9.8.1, 10.8.1, 11.8.1, 12.8.1,13.8.1, 14.8.1, 15.8.1, 16.8.1, 1.1.2, 2.1.2, 3.1.2, 4.1.2, 5.1.2,6.1.2, 7.1.2, 8.1.2, 9.1.2, 10.1.2, 11.1.2, 12.1.2, 13.1.2, 14.1.2,15.1.2, 16.1.2, 1.2.2, 2.2.2, 3.2.2, 4.2.2, 5.2.2, 6.2.2, 7.2.2, 8.2.2,9.2.2, 10.2.2, 11.2.2, 12.2.2, 13.2.2, 14.2.2, 15.2.2, 16.2.2, 1.3.2,2.3.2, 3.3.2, 4.3.2, 5.3.2, 6.3.2, 7.3.2, 8.3.2, 9.3.2, 10.3.2, 11.3.2,12.3.2, 13.3.2, 14.3.2, 15.3.2, 16.3.2, 1.4.2, 2.4.2, 3.4.2, 4.4.2,5.4.2, 6.4.2, 7.4.2, 8.4.2, 9.4.2, 10.4.2, 11.4.2, 12.4.2, 13.4.2,14.4.2, 15.4.2, 16.4.2, 1.5.2, 2.5.2, 3.5.2, 4.5.2, 5.5.2, 6.5.2, 7.5.2,8.5.2, 9.5.2, 10.5.2, 11.5.2, 12.5.2, 13.5.2, 14.5.2, 15.5.2, 16.5.2,1.6.2, 2.6.2, 3.6.2, 4.6.2, 5.6.2, 6.6.2, 7.6.2, 8.6.2, 9.6.2, 10.6.2,11.6.2, 12.6.2, 13.6.2, 14.6.2, 15.6.2, 16.6.2, 1.7.2, 2.7.2, 3.7.2,4.7.2, 5.7.2, 6.7.2, 7.7.2, 8.7.2, 9.7.2, 10.7.2, 11.7.2, 12.7.2,13.7.2, 14.7.2, 15.7.2, 16.7.2, 1.8.2, 2.8.2, 3.8.2, 4.8.2, 5.8.2,6.8.2, 7.8.2, 8.8.2, 9.8.2, 10.8.2, 11.8.2, 12.8.2, 13.8.2, 14.8.2,15.8.2, 16.8.2, 1.1.3, 2.1.3, 3.1.3, 4.1.3, 5.1.3, 6.1.3, 7.1.3, 8.1.3,9.1.3, 10.1.3, 11.1.3, 12.1.3, 13.1.3, 14.1.3, 15.1.3, 16.1.3, 1.2.3,2.2.3, 3.2.3, 4.2.3, 5.2.3, 6.2.3, 7.2.3, 8.2.3, 9.2.3, 10.2.3, 11.2.3,12.2.3, 13.2.3, 14.2.3, 15.2.3, 16.2.3, 1.3.3, 2.3.3, 3.3.3, 4.3.3,5.3.3, 6.3.3, 7.3.3, 8.3.3, 9.3.3, 10.3.3, 11.3.3, 12.3.3, 13.3.3,14.3.3, 15.3.3, 16.3.3, 1.4.3, 2.4.3, 3.4.3, 4.4.3, 5.4.3, 6.4.3, 7.4.3,8.4.3, 9.4.3, 10.4.3, 11.4.3, 12.4.3, 13.4.3, 14.4.3, 15.4.3, 16.4.3,1.5.3, 2.5.3, 3.5.3, 4.5.3, 5.5.3, 6.5.3, 7.5.3, 8.5.3, 9.5.3, 10.5.3,11.5.3, 12.5.3, 13.5.3, 14.5.3, 15.5.3, 16.5.3, 1.6.3, 2.6.3, 3.6.3,4.6.3, 5.6.3, 6.6.3, 7.6.3, 8.6.3, 9.6.3, 10.6.3, 11.6.3, 12.6.3,13.6.3, 14.6.3, 15.6.3, 16.6.3, 1.7.3, 2.7.3, 3.7.3, 4.7.3, 5.7.3,6.7.3, 7.7.3, 8.7.3, 9.7.3, 10.7.3, 11.7.3, 12.7.3, 13.7.3, 14.7.3,15.7.3, 16.7.3, 1.8.3, 2.8.3, 3.8.3, 4.8.3, 5.8.3, 6.8.3, 7.8.3, 8.8.3,9.8.3, 10.8.3, 11.8.3, 12.8.3, 13.8.3, 14.8.3, 15.8.3, 16.8.3, 1.1.4,2.1.4, 3.1.4, 4.1.4, 5.1.4, 6.1.4, 7.1.4, 8.1.4, 9.1.4, 10.1.4, 11.1.4,12.1.4, 13.1.4, 14.1.4, 15.1.4, 16.1.4, 1.2.4, 2.2.4, 3.2.4, 4.2.4,5.2.4, 6.2.4, 7.2.4, 8.2.4, 9.2.4, 10.2.4, 11.2.4, 12.2.4, 13.2.4,14.2.4, 15.2.4, 16.2.4, 1.3.4, 2.3.4, 3.3.4, 4.3.4, 5.3.4, 6.3.4, 7.3.4,8.3.4, 9.3.4, 10.3.4, 11.3.4, 12.3.4, 13.3.4, 14.3.4, 15.3.4, 16.3.4,1.4.4, 2.4.4, 3.4.4, 4.4.4, 5.4.4, 6.4.4, 7.4.4, 8.4.4, 9.4.4, 10.4.4,11.4.4, 12.4.4, 13.4.4, 14.4.4, 15.4.4, 16.4.4, 1.5.4, 2.5.4, 3.5.4,4.5.4, 5.5.4, 6.5.4, 7.5.4, 8.5.4, 9.5.4, 10.5.4, 11.5.4, 12.5.4,13.5.4, 14.5.4, 15.5.4, 16.5.4, 1.6.4, 2.6.4, 3.6.4, 4.6.4, 5.6.4,6.6.4, 7.6.4, 8.6.4, 9.6.4, 10.6.4, 11.6.4, 12.6.4, 13.6.4, 14.6.4,15.6.4, 16.6.4, 1.7.4, 2.7.4, 3.7.4, 4.7.4, 5.7.4, 6.7.4, 7.7.4, 8.7.4,9.7.4, 10.7.4, 11.7.4, 12.7.4, 13.7.4, 14.7.4, 15.7.4, 16.7.4, 1.8.4,2.8.4, 3.8.4, 4.8.4, 5.8.4, 6.8.4, 7.8.4, 8.8.4, 9.8.4, 10.8.4, 11.8.4,12.8.4, 13.8.4, 14.8.4, 15.8.4, 16.8.4, 1.1.5, 2.1.5, 3.1.5, 4.1.5,5.1.5, 6.1.5, 7.1.5, 8.1.5, 9.1.5, 10.1.5, 11.1.5, 12.1.5, 13.1.5,14.1.5, 15.1.5, 16.1.5, 1.2.5, 2.2.5, 3.2.5, 4.2.5, 5.2.5, 6.2.5, 7.2.5,8.2.5, 9.2.5, 10.2.5, 11.2.5, 12.2.5, 13.2.5, 14.2.5, 15.2.5, 16.2.5,1.3.5, 2.3.5, 3.3.5, 4.3.5, 5.3.5, 6.3.5, 7.3.5, 8.3.5, 9.3.5, 10.3.5,11.3.5, 12.3.5, 13.3.5, 14.3.5, 15.3.5, 16.3.5, 1.4.5, 2.4.5, 3.4.5,4.4.5, 5.4.5, 6.4.5, 7.4.5, 8.4.5, 9.4.5, 10.4.5, 11.4.5, 12.4.5,13.4.5, 14.4.5, 15.4.5, 16.4.5, 1.5.5, 2.5.5, 3.5.5, 4.5.5, 5.5.5,6.5.5, 7.5.5, 8.5.5, 9.5.5, 10.5.5, 11.5.5, 12.5.5, 13.5.5, 14.5.5,15.5.5, 16.5.5, 1.6.5, 2.6.5, 3.6.5, 4.6.5, 5.6.5, 6.6.5, 7.6.5, 8.6.5,9.6.5, 10.6.5, 11.6.5, 12.6.5, 13.6.5, 14.6.5, 15.6.5, 16.6.5, 1.7.5,2.7.5, 3.7.5, 4.7.5, 5.7.5, 6.7.5, 7.7.5, 8.7.5, 9.7.5, 10.7.5, 11.7.5,12.7.5, 13.7.5, 14.7.5, 15.7.5, 16.7.5, 1.8.5, 2.8.5, 3.8.5, 4.8.5,5.8.5, 6.8.5, 7.8.5, 8.8.5, 9.8.5, 10.8.5, 11.8.5, 12.8.5, 13.8.5,14.8.5, 15.8.5, 16.8.5, 1.1.6, 2.1.6, 3.1.6, 4.1.6, 5.1.6, 6.1.6, 7.1.6,8.1.6, 9.1.6, 10.1.6, 11.1.6, 12.1.6, 13.1.6, 14.1.6, 15.1.6, 16.1.6,1.2.6, 2.2.6, 3.2.6, 4.2.6, 5.2.6, 6.2.6, 7.2.6, 8.2.6, 9.2.6, 10.2.6,11.2.6, 12.2.6, 13.2.6, 14.2.6, 15.2.6, 16.2.6, 1.3.6, 2.3.6, 3.3.6,4.3.6, 5.3.6, 6.3.6, 7.3.6, 8.3.6, 9.3.6, 10.3.6, 11.3.6, 12.3.6,13.3.6, 14.3.6, 15.3.6, 16.3.6, 1.4.6, 2.4.6, 3.4.6, 4.4.6, 5.4.6,6.4.6, 7.4.6, 8.4.6, 9.4.6, 10.4.6, 11.4.6, 12.4.6, 13.4.6, 14.4.6,15.4.6, 16.4.6, 1.5.6, 2.5.6, 3.5.6, 4.5.6, 5.5.6, 6.5.6, 7.5.6, 8.5.6,9.5.6, 10.5.6, 11.5.6, 12.5.6, 13.5.6, 14.5.6, 15.5.6, 16.5.6, 1.6.6,2.6.6, 3.6.6, 4.6.6, 5.6.6, 6.6.6, 7.6.6, 8.6.6, 9.6.6, 10.6.6, 11.6.6,12.6.6, 13.6.6, 14.6.6, 15.6.6, 16.6.6, 1.7.6, 2.7.6, 3.7.6, 4.7.6,5.7.6, 6.7.6, 7.7.6, 8.7.6, 9.7.6, 10.7.6, 11.7.6, 12.7.6, 13.7.6,14.7.6, 15.7.6, 16.7.6, 1.8.6, 2.8.6, 3.8.6, 4.8.6, 5.8.6, 6.8.6, 7.8.6,8.8.6, 9.8.6, 10.8.6, 11.8.6, 12.8.6, 13.8.6, 14.8.6, 15.8.6, 16.8.6,1.1.7, 2.1.7, 3.1.7, 4.1.7, 5.1.7, 6.1.7, 7.1.7, 8.1.7, 9.1.7, 10.1.7,11.1.7, 12.1.7, 13.1.7, 14.1.7, 15.1.7, 16.1.7, 1.2.7, 2.2.7, 3.2.7,4.2.7, 5.2.7, 6.2.7, 7.2.7, 8.2.7, 9.2.7, 10.2.7, 11.2.7, 12.2.7,13.2.7, 14.2.7, 15.2.7, 16.2.7, 1.3.7, 2.3.7, 3.3.7, 4.3.7, 5.3.7,6.3.7, 7.3.7, 8.3.7, 9.3.7, 10.3.7, 11.3.7, 12.3.7, 13.3.7, 14.3.7,15.3.7, 16.3.7, 1.4.7, 2.4.7, 3.4.7, 4.4.7, 5.4.7, 6.4.7, 7.4.7, 8.4.7,9.4.7, 10.4.7, 11.4.7, 12.4.7, 13.4.7, 14.4.7, 15.4.7, 16.4.7, 1.5.7,2.5.7, 3.5.7, 4.5.7, 5.5.7, 6.5.7, 7.5.7, 8.5.7, 9.5.7, 10.5.7, 11.5.7,12.5.7, 13.5.7, 14.5.7, 15.5.7, 16.5.7, 1.6.7, 2.6.7, 3.6.7, 4.6.7,5.6.7, 6.6.7, 7.6.7, 8.6.7, 9.6.7, 10.6.7, 11.6.7, 12.6.7, 13.6.7,14.6.7, 15.6.7, 16.6.7, 1.7.7, 2.7.7, 3.7.7, 4.7.7, 5.7.7, 6.7.7, 7.7.7,8.7.7, 9.7.7, 10.7.7, 11.7.7, 12.7.7, 13.7.7, 14.7.7, 15.7.7, 16.7.7,1.8.7, 2.8.7, 3.8.7, 4.8.7, 5.8.7, 6.8.7, 7.8.7, 8.8.7, 9.8.7, 10.8.7,11.8.7, 12.8.7, 13.8.7, 14.8.7, 15.8.7 and 16.8.7.

Exemplary bis esters include bis(pivaloyloxymethyl)PMEA (i.e.bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine),bis(pivaloyloxymethyl)HPMPC, bis(pivaloyloxymethyl)D4AMPI,bis(pivaloyloxymethyl)D4TMPI, bis(N-ethylmorpholino)PMEA,bis(N-ethylmorpholino)HPMPC, bis(Nethylmorpholino)PMPDAP,bis(N-ethylmorpholino)HPMPA, bis(N-ethylmorpholino)PMEG,bis(N-ethylmorpholino)D4AMPI, bis(N-ethylmorpholino)D4TMPI,bis(phenyl)PMEA, bis(phenyi)HFMPC, bis(phenyl)HPMPA, bis(phenyl)D4AMPI,bis(phenyl)D4TMPI, bis(t-butyl)PMEA; bis(t-butyl)D4AMPI,bis(t-butyl)D4TMPNI, bis(t-butyl)HPMPC, bis(2-ethoxyphenyl)PMEA,bis(2-ethoxyphenyl)HPMPC, bis(4-fluorophenyl)PMEA,bis(4-fluorophenyl)HPMPC, bis(3,5-dimethoxyphenyl)PMEA,bis(3,5-dimethoxyphenyl)HPMPC and the like. L¹ is an amino acid whichis, in general, esterified at free α-carboxyl group(s) by R⁴, or is adipeptide, tripeptide or oligopeptide which is optionally esterified atthe free α-carboxyl group by R⁴. L² is an ester or thioester group.Suitable L² esters (and the corresponding thioesters) include methylester, ethyl ester, propyl ester, isopropyl ester, butyl ester, t-butylester, phenyl ester, bernzyl ester, N-ethylmorpholino ester(—O—CH₂—CH₂—N[(CH₂)₂(CH₂)₂]O), pivaloyloxymethyl ester(—O—CH₂—O—C(O)—C(CH₃)₃) and the like. The suitability of the presence orabsence of any particular L² or R⁴ group is determined by stabilityand/or bioavailability assays (e.g., stability assay in aqueousconditions such as low pH/intestinal lumen conditions or assay in thepresence of cellular extracts containing esterases or by bioavailabilityassay using animal models) known in the art. These assays are routinelyperformed by the skilled artisan.

The bis ester is then converted to a monoester by chemical hydrolysis inbase or acid according to the bis ester used. For example, treatmentwith NaOH (0.5 to 2 N) or NH₄OH in a solvent such as THF(tetrahydrofuran), dioxane or an alcohol for 1 to 24 hours at 22° to 90°is suitable for most esters. The choice of solvent will depend on thecharacteristics of the bis ester used. The stability of the ester groupsof phosphonate bis esters and phosphonate bis thioesters towardhydrolysis is unequal and provides a means for obtaining the monoester.Selection of hydrolysis conditions is determined by routine testing.Alkaline hydrolysis yields the phosphonate monoester and a correspondingalcohol or phenol. L¹ is then linked to the monoester or monothioesterusing reagents and conditions (i.e., a 1:1 mixture of triphenylphosphine(PPh₃) and 2,2′-dipytidyl disulfide in a suitable solvent such aspyridine or DMF) essentially as described for synthesis of bis amidates.

Nucleoside bis esters of formulas VI, VII and VIII compounds are shownin FIGS. 4-7. 3′,4′-Unsaturated nucleosides that are used as a startingmaterial was previously described (Zemlicka, et al J Am Chem Soc (1970)92:4744-4745). 4′-Modified nucleosides have also been described (Yang,et al Tet Lett (1992) 33: 41-44; Yang, et al Tet Lett (1992) 33: 37-40;Prisbe, et al Nucleosides and Nucleotides as Antitumor and AntiviralAgents (1993) Plemun Press, New York, Chu, C. K. et al eds., p.101-113). The phosphonate ester is condensed with the unsaturatednucleoside using an oxidizing agent such as MCPBA (m-chloroperoxybenzoicacid), IBr or N-iodosuccinimide (NIS). The choice of a particularoxidizing agent will be guided by considerations such as the type ofheterocyclic base or sugar substituent that is present. For example, IBrmay not be generally compatible with a substituent such as azide (at R²⁷or R³³) or 1-propynyl (at B). In these cases, NIS or MCPBA is used. Afurther example is reduction of the 2′,3′-double bond using H₂/Pd/C,which is generally not compatible with an alkynyl group that can bepresent at B. In this case, the alkynyl group would be added to anappropriate heterocyclic base (a purine such as 7-deaza-7-iodoadenine or7-deaza-7-iodoguanine, etc or a pyrimidine such as 5-iodocytosine,5-iodouracil, uracil, etc) that is later converted to the alkynylderivative (7-deaza-7-(1-propynyl)adenine, 5-(1-propynyl)uracil, etc)using an alkyne such as propyne and palladium (Ser. No. 08/050,698;PCT/US92/10115; Hobbs et al, J Org Chem (1989) 54:3420-3422). For FIGS.3-7, R³³ is H, OH, TBSO, halogen, cyano, CH₂N₃, C₁-C₄ alkyl, C₁-C₄alkoxy (including OCH₃), CH₂OH or azido; R³⁴ is H, OH halogen (fluorineis preferred), azide, O-alkyl (C₁-C₆ including O-methyl and O-ethyl),S-alkyl (C₁-C₆ including S-methyl and S-ethyl) and O-alkenyl (includingO-allyl); R is as defined above, except that for the structure(RO)₂P(O)—CH₂—OH, R is not hydrogen, and R includes C₁-C₂₀ alkoxyacylgroups including methoxyacyl (pivaloyloxymethyl, adamantoyl oxymethyland the like) and ethoxyacyl (pivaloyloxyethyl and the like) moieties;TBSO is t-butyldimethylsilyl ether. The phosphonates and monoestersshown in FIGS. 4-7 are converted to bis amidates or mixed amidate estercompounds using reagents and conditions (e.g., a 1:1 mixture oftriphenylphosphine (PPh₃) and 2,2′-dipyridyl disulfide in a suitablesolvent such as pyridine or DMF) essentially as described above.

Mixed bis amidate synthesis. Synthesis of compounds of formula Id whereL¹ and L² are both amino acids or where L¹ is an amino acid and L² is anamine (NH₂, NHR⁶, N(R⁶)₂) but are not both the same is accomplished bydirect conversion as described above for bis amidates followed byseparation of the final products. Another method to synthesize mixed bisamidates is amidation of an appropriate phosphonate monoester to give acompound of formula Id, followed by removal of the ester group underconditions that do not remove the first amide. Synthesis of phosphonatemonoester compounds has been described (EP 481 214). This compound isthen converted to a mixed bis amide by condensation with a second aminoacid to yield the final product as described (i.e., using a 1:1 mixtureof triphenylphosphine and 2,2′-dipyridyl disulfide).

Mono amidate synthesis. Synthesis of compounds of formula Ib where L¹ isan amino acid and X¹ is O (oxygen) is accomplished essentially asdescribed for bis amidate synthesis using a cyclic nucleotide analogsuch as cHPMPC (cyclic HPMPC), cHPMPA, cHPMPDAP, cHPMPG and the like.Cyclic HPMP series compounds (cHPMFC, etc) are prepared by directdehydration of the corresponding HPMP nucleotide analog using DCC(dicyclohexylcarbodiimide) or using4-morpholino-N,N′-dicyclohexylcarboxamide as described, (Ho et al MolPharmacol (1992) 41:197-202). The cyclic phosphonate is condensed withan optionally protected amino acid ester in the presence of a 1:1mixture of triphenylphosphine and 2,2′-dipyridyl disulfide in a suitablesolvent such as pyridine or DMF.

Synthesis of formula Ib compounds where X¹ is S is accomplished as shownin FIG. 1. Conversion of the six-membered heterocycle to an amidate isaccomplished in essentially the same manner as described (i.e., usingtriphenylphosphine and 2,2′-dipyridyl disulfide).

Synthesis of formula IV compounds where R²⁶ is S and R²⁵ and R²⁹ are Ois accomplished as shown in FIG. 3. The starting material is synthesizedby reaction of thiolacetic acid (Aldrich Cat. No. T3,080-5);bromoacetaldehyde diethyl acetal (Aldrich Cat. No. 12,398-6) andpotassium tert-butoxide (Aldrich Cat. No. 15,667-1) in DMF. Synthesis of1 where R³⁴ is H is accomplished using neat (EtO)₃CH. Synthesis of 1where R³⁴ is CH₂CN or CF₃ is accomplished using (EtO)₃CH₂CN or (EtO)₃CF₃in methylene chloride with a catalytic acid (such as p-toluenesulfonicacid). Conversion of the thiaorthoester 1 to the phosphonate 2 isaccomplished using an add such as tosic acid or perchioric acid incatalytic amounts. The resulting bis ester is then converted to a bisamidate in essentially the same manner as described (i.e., usingtriphenylphosphine and 2,2′-dipyridyl disulfide). Mixed ester-amidatecompounds are obtained by removing a single ester from the bis esterusing base (NaOH, NH₄OH, etc) as described. The phosphonate 3 isobtained by treatment with a base such as TMSBr or TMSI in a solvent(such as methylene chloride, DMF or acetonitrile) in the presence oflutidine (where R is alkyl, aryl or substituted aryl, acyloxyalkyl suchas isopropyl, phenyl, 2-ethoxyphenyl) or by treatment with Pd/C/H₂(where R is alkaryl or substituted alkaryl such as benzyl and the like).R³⁴ in FIG. 3 is H, CF₃ or CH₂CN.

Protected heterocyclic base compounds. The present invention includesnucleotide analogs that comprise a protected heterocyclic base. Thesecompounds are useful as synthetic intermediates and/or, as therapeuticagents per se. Protected heterocyclic base compounds structures, theirisomers, tautomers and the salts of such compounds having the formula(R³⁵O)₂P(O)-Z-B¹, (L^(1A)O)(L^(2A)O)P(O)-Z-B¹, (HO)₂P(O)-Z-B¹

where L^(1A) is L¹, R or NHR⁴⁰, wherein R⁴⁰ is C₁-C₂₀ alkyl; L^(2A) isL², R³⁵ or NHR⁴⁰; B¹ is a protected heterocycLic base having the formulaXa, XIa, XIb, XIIa or XIIIa previously defined.

Suitable exemplary Z include compounds of formulas IV, V, VI, VII, VIII,—CH₂—O—CH₂—CH₂—, —CH₂—O—C#H(CH₃)—CH₂— and —CH₂—O—C#H(CH₂OH)—CH₂— havinga heterocyclic base with an exocyclic amine can be converted tonucleotide analog amidates or esters comprising a protected heterocyclicbase either by reacting the nucleotide analog amidate or ester withR³⁶C(O)Cl or (CH₃O)₂CHR³⁸. Protected heterocyclic bases include specieshaving protecting groups at exocyclic amine groups such as the N⁴-amineof cytosine, the N⁶-amine of adenine and the N²-amine of guanine. Thephosphonate moiety of compounds containing B¹ may be present as anester, an amidate or as the free acid.

Bases having NHR⁴⁰ at an exocyclic amine are synthesized to obtain aprotected pyrimidine or purine essentially as described (Gilliam Anal.Biochem. (1986) 157:199; Gallo-Rodriguez J. Med. Chem. (1994) 37:636;Maillard J. Pharm. Sci. (1994) 83:46).

The exemplary reaction schemes used to synthesize protected heterocyclicbase compounds shown below utilize cHPMPC as an example. Analogousreactions will generate compounds comprising other Z moieties such as—CH₂—O—CH₂—CH₂— or —CH₂—O—CH(CH₃)—CH₂— linked to B¹. Phosphonate alkyland aryl esters of compounds comprising B¹ are prepared, using HPMPC andcHPMPC as an example, according to the following procedures

wherein R³⁶ is as defined above. Either procedure is readily adapted tosynthesizing compounds containing protected heterocyclic bases otherthan cytosine, e.g., adenine, guanine, 2,6-diaminopurine or2-aminopurine. Exemplary R³⁵ and/or R³⁶, which can be the same ordifferent, include phenyl, substituted phenyl, —C₁₀H₁₅ (where C₁₀H₁₅ isadamantoyl), —CH₂—C₆H₅, —C₆H₅, —C(CH₃)₃, —CH(CH₃)₂, —CH₂CH₃, methyl,ethyl, butyl, t-butyl, heptanyl, nonanyl, undecanyl, lauryl, steryl,undecenyl and the like. The amide linkage is conveniently formed byreaction of the acyl chloride with the exocyclic amine linked to thebase. When R¹ is linked to the free phosphonate the resulting ester willcomprise a single isomer or a scalemic mixture at the phosphorus atom.Low temperature reaction conditions (lower than about −20°, e.g., about−20° to about 40° C. or about −40° to about −80° C.) tend to favorsingle isomer products, while reaction at higher temperatures (aboveabout −20°, e.g. −20° to 40° C.) generally results in a scalemic mix.When a scalemic mixture is obtained, the isomers can be convenientlyseparated by, for example, HPLC, although the mixture can be used, forexample, as a synthetic intermediate or as an active antimicrobialagent, without resolution. Synthesis of the phenyl ester of cHPMPC at−78° C. by reaction of the chloridate and phenoxide yielded a scalemicmixture consisting of about ≧90% of the product as one isomer (isomer#1) at the phosphorus atom while the remaining ˜≦10% was present as theother isomer (isomer #2). The scalemic mixture was converted to isomer#2 (≧90%) by incubation at room temperature for about 10 minutes (about10 to 30 minutes is generally suitable) with a catalytic amount ofsodium phenoxide in DMF. This method can be used to convert one isomerof cHPMP-B or cHPMP-B¹ (such as cHFMPC or cHPMPA) aryloxy or alkoxyester to the other isomer with catalytic amounts of the correspondingaryloxide ion or alkoxide ion.

The cHFMPC pivaloyloxymethyl ester synthesis yields a scalemic mixtureat the phosphorus atom. The mixture was separated by HIPLC into the twoisomers which were then exposed to an rat intestinal homogenate or to arat intestinal wash. One of the isomers was converted to cHPMPC afterincubation in the homogenate while the other isomer was converted toHPMPC pivaloyloxymethyl monoester. Both isomers were converted to HPMPCpivaloyloxymethyl monoester after incubation in the intestinal wash.These results suggested that (1) in at least some cases, enzyme activitycan have a differential effect on the metabolic fate of a cHPMPC esterdepending on which phosphorus isomer is present and (2) chemicalactivity (i.e., the acidity of the intestinal wash) can affect themetabolic fate of a given compound in a manner that differs from enzymeactivity.

A method to obtain heterocyclic bases comprising the C(O)R³⁶ protectinggroup is accomplished as follows using the acyl chloride (R³⁶C(O)Cl)using HPMPC and cHPMPC as an example

wherein Tr is the hydroxyl protecting group trityl. The detritylationstep is accomplished by acid treatment, such as 80% acetic acid at about10° to 60° C. for 1-2 hours. The R³⁵ moiety is removed using a Lewisacid such as TMSBr to yield the free phosphonate.

Phosphonate compounds comprising B¹ and a C₂-C₂₀ 1-acyloxy-1-alkyl or aC₄-C₂₀ 1-acyloxy-1-alkyl-1-aryl ester group are prepared as follows

wherein R³⁷ is C₁-C₂₀ alkyl which is unsubstituted or substituted bysubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl (1 to 3 halogen atoms), cyano,nitro, OH, O, NH and halogen (including ethyl, propyl, isopropyl,t-butyl, isobutyl and adamantoyl), or C₃-C₁₀ aryl which is unsubstitutedor substituted by substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl (1 to 3 halogenatoms), cyano, nitro, OH, O, N and halogen (including phenyl, and 3- or4-pyridyl).

The amine protecting group ═CR⁴¹N(R³⁸)₂ is incorporated into anexocyclic amine to yield protected heterocyclic base compounds asfollows

Exemplary R³⁸ alkyl groups include methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl and cyclobutyl. In general, both R³⁸ alkylgroups will be the same. The reaction can be carried out in dry DMF atroom temperature (about 20-30° C.) as previously described (Kerr et alJ. Pharm. Sci. (1994) 83:582; Kerr et al J. Med. Chem. (1992) 35:1996),or DMF can be substituted with CH₃CN and 4 Å molecular sieves. Exemplarycompounds include species where R is hydrogen, alkyl (including ethyl,propyl, isopropyl), aryl (including phenyl) or acyloxymethyl. Protectedheterocyclic bases where R⁴¹ is hydrogen are stable under neutralanhydrous conditions and are generally labile under acidic aqueousconditions. When R⁴¹ is methyl, the protecting group is more stable toaqueous acidic or basic conditions.

Compounds containing a protected heterocyclic base and 1 or 2 aminoacids, dipeptides or oligopeptides attached to the phosphorus atom viaan amidate linkage are obtained as described for synthesis ofbis-amidate or amidate-ester compounds.

Table 5A lists R³⁵ ester and L¹ amidate moieties that can beincorporated into the phosphorus atom of both cyclic Z moieties (such ascHPMPC comprising a protected heterocyclic base or cHPMPC) or linear Zmoieties (such as HPMPC comprising a protected heterocyclic base or PMEAcomprising a protected heterocyclic base or PMEA). Esters of structures1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting a nucleotideanalog (such as cHPMPC) the corresponding halide (chloride or acylchloride and the like) and N,N-dicylohexyl-N-morpholine carboxamidine(or another base such as DBU, triethylamine, CsCO₃, N,N-dimethylanilineand the like) in DMF (or other solvent such as acetonitrile orN-methylpyrrolidone). Esters of structures 5-7, 11, 12, 21, and 23-26are synthesized by reaction of the alcohol or alkoxide salt (or thecorresponding amines in the case of compounds such as 13, 14 and 15)with a nucleotide analog monochlorophosphonate or dichlorophosphonate(such as cHPMPC monochlorophosphonate or PMEA dichlorophosphonate) oranother activated phosphonate.

TABLE 5A  1. —CH₂—C(O)—N(R⁷)₂*  2. —CH₂—S(O)(R⁷)  3. —CH₂—S(O)₂(R⁷⁾  4.—CH₂—O—C(O)—CH₂—CH₂—C₆H₅  5. 3-cholesteryl  6. 3-pyridyl  7.N-ethylmorpholino  8. —CH₂—O—C(O)—C₆H₅  9. —CH₂—O—C(O)—CH₂CH₃ 10.—CH₂—O—C(O)—C(CH₃)₃ 11. —CH₂—CCl₃ 12. —C₆H₅ 13. —NH—CH₂—C(O)O—CH₂CH₃ 14.—N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR⁴⁰ 16. —CH₂—O—C(O)—C₁₀H₁₅ 17.—CH₂—O—C(O)—CH(CH₃)₂ 18. —CH₂—C#H(OC(O)CH₂R⁷)—CH₂—(OC(O)CH₂R⁷)* 19.

20.

21.

22.

23.

24.

25.

26.

*Each R⁷ is the same or different (includes methyl, ethyl, propyl,isopropyl and t—butyl).

All citations are hereby expressly incorporated by reference. Thefollowing examples are illustrative and do not limit the scope of thisinvention.

EXAMPLE 1 Synthesis of Phosphonate Amidate Compounds

The compounds of structural formula Id shown are in Table 6 (bis(glycylbenzyl ester)PMEA (compound Ex 4), bis(alanyl benzyl ester)PMEA (Ex 1),bis(phenylalanyl benzyl ester)PMEA (Ex 5), etc. Compounds Ex 1-Ex 12were synthesized by the following procedure. PMEA (Z-B=—CH₂—O—CH₂—CH₂—B,where B is adenin-9-yl) (0.3 g; 1.1 mmol) and amino acid ester.HCl (2.2mmol; Sigma) were suspended in dry pyridine (6 mL) containingtriethylamine (0.3 mL; 22.2 mmol), followed by addition to a mixture offreshly prepared triphenylphosphine (3.3 mmol) and 2,2′-dipyridyldisulfide (3.3 mmol) in pyridine (3 mL). The mixture was stirred at roomtemperature overnight, concentrated and partitioned between methylenechloride and water. The organic solution was dried over MgSO₄,concentrated and purified by flash column chromatography on silica gel.

Ex 14 was synthesized using freshly prepared triphenylphosphine (6.0mmol) and 2,2′-dipyridyl disulfide (6.0 mmol) in pyridine (20 mL) atroom temperature to which PMEA (2.0 mmol) was added. The suspension wasstirred for 10 min. and ethyl sarcosine HCl (N-methylglycine HCl ethylester; 1.2 g, 8.0 mmol) was added. The suspension was warmed to 90° C.and stirred for 24 hours. Crude product was concentrated by rotaryevaporation and purified by silica flash chromatography (mobile phase 1%methanol gradient to 20% methanol/80% methylene chloride).

Compound Ex 13 was synthesized in a similar manner using PMEA andphenylalanine N-ethylmorpholino ester.

TABLE 6 Compound L¹ Ex 1 —NH—CH(CH₃)—C(O)OCH₂C₆H₅ Ex 2—NH—CH(CH₂C₆H₅)—C(O)OCH₂C₆H₅ Ex 3 —NH—CH(CH₂CH(CH₃)₂)—C(O)OCH₂C₆H₅ Ex 4—NH—CH₂—C(O)OCH₂C₆H₅ Ex 5 —NH—CH(CH₃)—C(O)OC₂H₅ Ex 6—NH—CH(CH₂CH(CH₃)₂)—C(O)OC₂H₅ Ex 7 —NH—CH₂—C(O)OC₂H₅ Ex 8—NH—CH(CH₂C₆H₅)—C(O)OC(CH₃)₃ Ex 9 —NH—CH(CH₂CH(CH₃)₂)—C(O)OC(CH₃)₃ Ex 10—NH—CH(CH₃)—C(O)OC(CH₃)₃ Ex 11 —NH—CH₂—C(O)OC(CH₃)₃ Ex 12—NH—CH(CH₂C₆H₅)—C(O)OC₂H₅ Ex 13 —NH—CH(CH₂C₆H₅)C(O)O—(CH₂)₂—N[(CH₂)₂(CH₂)₂]O Ex 14 —N(CH₃)—CH₂—C(O)OC₂H₅

EXAMPLE 2 Antiviral Activity

Compounds were individually tested for activity against HSV-1 and/orHSV-2. HSV-2 (strain 414-92) was tested using MA 104 cells in thefollowing assay protocol. 96-Well plates were seeded with 1×10⁴ MA 104cells per well using 200 μL minimal essential medium (MEM) containing10% calf serum per well, and incubated overnight at 37° C. The compoundswere dissolved in MEM Earle's Salts without serum. The medium wasremoved by-aspiration and 100 μL MEM Earle's Salts without serum wasadded to the wells. Serial 3-fold dilutions of the compounds wereprepared by serial transfer of 50 μL of medium from wells containingcompound to wells lacking compound. The plates were incubated 15 minutesat 37° C. followed by addition of 100 PFU/well of virus in MEM Earle'sSalts with 2% fetal bovine serum. The plates were then incubated at 37°C. for three days until approximately 90% of the cells in virus infectedcontrol wells containing no compound were killed. Following incubation,medium was aspirated and the wells were washed with sterile PBS. 100 μL0.5% crystal violet in 20% methanol was then added to the wells for 5minutes, aspirated and the wells were washed two or three times withdistilled water. 200 μL of 0.01 N HCl was added to the wells and theabsorbance of each well at 595 nm was determined. The results, shown inTable 6, were expressed as the IC₅₀, the concentration (μM) thatinhibits cell killing mediated by HSV-2 by 50%. IC₅₀ values varied from2 μM to >100 μM compared to an IC₅₀ for PMEA of 21 μM. Thus, some of thecompounds were more active against HSV-1 than PMEA. The toxicity of thecompounds were expressed as the CC₅₀, the concentration that kills 50%of uninfected cells.

The compounds were also tested for activity against the KOS strain ofHSV-1 in VERO cells. The results, shown in Table 7, were expressed asthe EC₅₀, the concentration (μM) that inhibits cell killing mediated byHSV-2 by 50%. EC₅₀ values varied from 2 μM to >200 μM compared to anEC₅₀ for PMEA of 138 μM. Thus, some of the compounds were more activeagainst HSV-2 than PMEA.

TABLE 7 HSV-1 HSV-2 compound EC₅₀ IC_(5O) CC₅₀ Ex 7 >200 >100 >100 Ex 5 nt* >100 >100 Ex 6 20 33 >100 Ex 12 nt 20 80 Ex 11 >200 >100 >100 Ex10 >200 >100 >100 Ex 9 63 63 >100 Ex 8 3 9 20 Ex 4 nt 60 >100 Ex 1 nt20 >100 Ex 3 nt 2 30 Ex 2 nt 4 20 *nt—not tested

EXAMPLE 3 PMEA, Monophenyl Ester, Mono N-Ethylmorpholino-PhenylalanylPhosphoroamidate

Bis(phenyl)PMEA is selectively hydrolyzed to the monophenyl ester ofPMEA using NaOH in THF. The reaction mixture is neutralized with acid (1N HCl), and the monophenyl. PMEA is isolated by filtration. Theanhydrous monophenyl PMEA and 2 equivalents of a freshly prepared 1:1mixture of triphenylphosphine and 2,2′-dipyridyl disulfide in pyridineis condensed with 1 equivalent of phenylalanine N-ethyl-morpholino esterin triethylamine and pyridine to afford the title compound. The titlecompound is recovered by evaporation of the solvents under reducedpressure and purified by silica gel chromatography.

EXAMPLE 4 Antiviral Activity of PMEA Esters

PMEA and PMEA esters were tested for inhibition of cytopathic effects byHSV II in MA 104 cells as described except that CPE was determined afterincubation with virus by addition of 100 μL XTT, 1 mg/mL in deficientDME containing 25 μM PMF followed by measuring absorbance. The esterstested were bis(POM)PMEA, bis(phenyl)PMEA, monophenylPMEA,bis(3-dimethylaminophenyl)PMEA, bis(3-methoxyphenyl)PMEA,bis(2-carboethoxyphenyl)PMEA, bis(adamantoyl oxymethyl)PMEA,bis(4-fluorophenyl)PMEA and bis(2-ethoxyphenyl)PMEA. All of thecompounds tested were active, which indicated that the ester groups wereremoved, thereby allowing free PMEA to inhibit virus replication and/orcytopathic effects. The IC₅₀ and CC₅₀ of PMEA in the assay was 19.3 μMand 2000 μM respectively and the IC₅₀ and CC₅₀ of bis(POM)PMEA in theassay was 0.5 μM and >10 μM respectively. IC₅₀ values for the mono andbis esters ranged from 1.1 μM to 67.5 μM and the CC₅₀ values ranged from70 μM to 500 μM.

EXAMPLE 5 Oral Bioavailability of Nucleotide Analog Amidates and PMEAEsters

Nucleotide analog amidates and nucleotide analogs are tested for theirbioavailabililty when adminnistered to cynomologous (or rhesus) monkeysby oral, subcutaneous or intramuscular routes. Bioavailability isdetermined by measuring PMEA levels in plasma or urine at differenttimes after administering the drug using radiolabeled (³H, ¹⁴C, etc)compound or, for compounds having adenine, essentially as described(Naesens, et al, Clin Chem (1992) 31:480485; Russell, et al, JChromatogr (Netherlands) (1991) 572:321-326). Radiolabeled compounds areobtained commercially (Moravek Biochemicals, Brea, Calif.) or bystandard procedures, such as catalytic hydrogen exchange for ³Hlabeling. Compounds such as bis(2-ethoxyphenyl)PMEA,bis(2-carboethoxyphenyl)PMEA, bis(O-benzylphenylalanyl)PMEA,bis(3,5-dimethoxyphenyl)PMEA, bis(4-fluorophenyl)PMEA, bis(adamantoyloxymethyl)PMEA, bis(phenyl)PMEA, bis(3-methoxyphenyl)PMEA are tested fororal bioavailability by administering about 10-30 mg/Kg (usually 15 to25 mg/Kg) containing about 20-50 μCi/Kg (usually about 40 μCi/Kg) ofradiolabeled compound, followed by withdrawing blood samples at severaltimes after administration (exemplary time points are 0.1, 0.25, 0.5,1.0, 1.5, 2.0, 2.5, 3.0, 4, 6, 12, 18, 24, 36, 48, 72, 96 hours afteradministration), obtaining plasma and determining the amount ofradiolabeled compound present per volume (about 0.1-1.0 mL) of serum.Oral bioavailability of the tested compounds is 2-80% (or any valuebetween 2% and 80% in 1% increments), preferably 10-80% and morepreferably 15 to 80%. The oral bioavailability of bis(POM)PMEA by thistype of assay is typically about 25% in monkeys and PMEA is about 2-4%(Balzarini et al, Animal Models in AIDS (1990) p. 131-138, Schellekens,H. et al. (ed), Elsevier Science Publications, Amsterdam) whilenucleotide analog amidates and nucleotide analogs (including mono- anddiesters) can have oral bioavailabilities of about 5%, 10%, 15%, 30%,40%, 50%, 60% or 80%.

Total radioactivity in plasma is determined by mixing about 200 μL ofplasma with a scintillation counting cocktail (such as 10 mL ofScinti-Safe plus LSC cocktail) and counting in a scintillation counter(usually for about 5-30 minutes). Detailed analysis of the radiochemicalcomposition is accomplished using about 350 μL of plasma, denaturingproteins in the serum (using about 700 μL 0.1% trifluoroacetic acid inacetonitrile for example), drying the resulting sample under reducedpressure, suspending the sample in an appropriate buffer (for exampleusing about 100 μL of 2% acetonitrile in 25 mM potassium phosphatebuffer with 10 mM tetrabutyl ammonium hydrogen phosphate (TBAHP), pH 6.0for HPLC analysis), centrifuging the sample and analyzing thesupernatant for individual radiolabeled species by reverse phase HPLC oncommercially available columns (The Separation Group, Hesperia, Calif.;Vydac C18, 5 μm, 250×4.6 mm column with an injection volume of about 50μL and a flow rate of about 1.0 mL/min. at about 35° C. using buffer for2 minutes followed by a linear gradient to about 65% acetonitrile in 25mM potassium phosphate buffer with 10 mM TBAHP, pH 6.0 over 13 aboutminutes). Radiolabel detection is accomplished using means such ascommercially available radioactive flow detection systems orscintillation counting systems (Packard, Meridian, Conn.).

Fluorescence detection of PMEA in plasma is accomplished by measuringfluorescence emission (420 nm, with excitation at about 236 nm) with adetector (model F2000, Spectra Physics, San Jose, Calif.) from the HPLCgradient essentially as described above (2 to 65% acetonitrile). Samplesfor analysis are prepared from plasma (200 μL) by protein precipitationwith TFA (400 μL 0.1% in acetonitrile), drying and conversion of adenineto N6-ethenoadenine in 200 μL of reaction buffer (0.34%chloroacetaldehyde, 100 mM sodium acetate, pH 4.5) for 40 minutes at 95°C. followed by HFLC analysis using 50 μL.

EXAMPLE 6 Bis(Adamantoyl Oxymethyl)PMEA Ester

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene; 1.53 g, 10 mmol) was added to asuspension of PMEA (1.365 g, 5 mmol) in DMF (25 mL). Adamantoyloxymethyl chloride (5.72 g, 25 mmnol) in DMF (25 mL) was added to thereaction mixture which was then stirred for four days at roomtemperature and the volatiles were removed under vacuum. The crudeproduct obtained after removal of the solvent was loaded onto a silicagel column and washed with 3% MeOH/CH₂Cl₂ to remove nonpolar impurities.1 g (30%) of bis(adamantoyl oxymethyl)PMEA ester was eluted in 8%MeOH/CH₂Cl₂. Adamantoyl oxymethyl chloride was obtained by conversion of1-adamantanecarbonyl chloride (Aldrich No. 11,772-2) with(CH₂O)_(n)/ZnCl₂ and has been described (Bodor, et al J Med Chem (1980)23:474-480).

EXAMPLE 7 Bis(Phenyl)PMEA and bis(2-Ethoxyphenyl)PMEA Esters

PMEA (2.0 g, 7.3 mmol), acetonitrile (20 mL), thionyl chloride (20 mL)and N,N-dimethylformamide (2 drops) were added to a 250 mL single neckround bottom flask equipped with a magnetic stirrer, water cooledcondenser and N₂ atmosphere. The flask was immersed in a 85° C. oil bathand the resulting suspension was stirred for two hours. The resultingsolution was then concentrated to dryness and acetonitrile (50 mL) wasadded to redissolve the crude chloridate.

To a separate 250 mL single neck round bottom flask equipped with amechanical stirrer, and N₂ atmosphere, phenol (3.25 g, 35 mmol),tetrahydrofuran (80 mL) and sodium hydride (1.4 g, 34 mmol, 60% (w/w)dispersion in mineral oil) was charged. After stirring for 30 minutes,the solution was cooled to −78° C. with a dry ice-acetone bath Theacetonitrile from the previous step was then added drop-wise at a ratethat the internal temperature did not rise above −76° C. After theaddition was complete, the resulting suspension was poured intosaturated aqueous NaHCO₃ (100 mL) and extracted with methylene chloride(3×150 mL). The combined organic extracts were washed with H₂O (100 mL),brine (100 mL) and dried with anhydrous Na₂SO₄. Concentration by rotaryevaporation afforded a yellow solid. Purification by recrystallization(ethyl acetate/hexanes) afforded pure bis(phenyl)PMEA (1.64 g, 53%).Bis(2-ethoxyphenyl)PMEA was made similarly using 2-ethoxyphenol in placeof phenol in 36% yield.

EXAMPLE 8 (R)-9-(2-Di-2 ethoxyphenylphosphonylmethoxypropyl) adenine

To a solution of 2-ethoxyphenol (45 mmol, 6.22 g) in pyridine (75 mL)was added (R)-9-(2-phosphonylmethoxypropyl adenine (PMPA, 15 mmol, 4.3g), creating a white suspension. A separate solution of 2,2′-dipyridyldisulfide (45 mmol, 9.91 g) and triphenyl phosphine (45 mmol, 11.81 g)in pyridine (75 mL) was added at 22° C. in a single portion to the whitesuspension. Then, triethylamine (30 mmol, 4.18 mL) was added in a singleportion to the entire mixture, which was stirred at 75° C. for 21 h(TLC:10% MeOH/EtoAc). The dark amber slurry was then coevaporated withtoluene (100 mL). It was then dissolved in dichloromethane (200 mL) andextracted twice with water (200 mL). The organic phase was dried(NaSO₄), filtered and concentrated (in vacuo) to a brown syrup (25.4 g).The syrup was purified by flash chromatography: 1-5% MeOH/EtoAc to eluteimpurities, then 6-12% MeOH/EtoAc (title compound elutes at 10-11%). Thedesired fractions were concentrated to afford 1.04 g of a brown solid.The solid was then recrystalized (EtoAc) to give the title compound (780mg, 12% yield) as a tan solid. HNMR (CDCl₃) δ 1.25 (d, J=7.5 Hz, 3H,CH₃), δ 1.46 (m, 6H (OCH₂CH₃)₂), 4H (OCH₂CH₃)₂), δ 3.9 (m, 2H, O—CH₂P),δ 4.04 (m, 1H, H-2′), δ 4.09-4.39 (m, 2H, H-1′), 7.24 (m, 8H, (C₆H₄)₂),7.92 (S, 1H, (C₈—H), 8.19 (S, 1H, C₂—H).

EXAMPLE 9 cHMPU

cHPMPU was synthesized by adding thionyl chloride (60 mL, 0.812 mmol,2.02 eq) dropwise to a suspension of disodium HPMPU (131 mg, 0.404 mmol)in N,N-dimethylformamide (1.25 mL) at ambient temperature. The resultinglight-yellow solution was stirred for 20 min at ambient temperature andthen concentrated to dryness (in vacuo, 45° C.). H₂O (2 mL) was addedand the resulting solution was concentrated to dryness. Methanol (4 mL)was added and the resulting solution was concentrated to dryness toafford the crude product as a light-yellow solid. Purification by silicaflash chromatography (mobile phase: 30% methanol: 70% CH₂Cl₂ gradient to50% methanol: 50% CH₂Cl₂) afforded pure cHPMPU in 69% yield as a whiteamorphous solid. ¹H NMR (300 MHz, D₂O) d 7.62 d (1H, J=7.1 Hz, CH═CH),5.82 d (1H, J=7.8 Hz, CH═CH), 4.30-3.71 nm (7H, CH₂CH(OCH₂P)CH₂OH), NHand OH not observed in D₂O. ¹³C NMR (75 MHz, D₂O) d, 169.6 s (4-C),155.1 s (2-C), 150.4 s (6-C), 104.2 s (5-C), 76.71 d (JP,C=3.6 Hz,2′-CH₂), 72.30 d (JP,C=6.2 Hz, 3′-CH₂), 67.90 d (JP,C=142.0 Hz, P-CH₂),50.71 s (1′-C). ³¹P NMR (121 MHz, D₂O) d 9.23 s.

EXAMPLE 10 cHPMPC Ethyl Ester

To a stirred solution of diethyl HFMPC (1.1 g) in DMF, NaH (115 mg) wasadded. After 15 min, the reaction mixture was quenched with acetic acid(1 eq). The solvents were removed under reduced pressure. The crudemixture was dissolved in CH₂Cl₂ and water. The organic layer was washedwith NaCl solution and the crude material obtained was purified on asilica gel column (elution with 5%-10% MeOH in CH₂Cl₂) to get cyclicethyl HPMPC (950 mg) as a diastereomeric mixture (approximately 70%).

EXAMPLE 11 cHPMPC Esters

To a stirred suspension of HPMPC (2.79 g) in DMF, thionylchloride (2.1mL) was added dropwise under anhydrous conditions and the mixture wasstirred for 1 hr. In another flask, sodium aryloxide (using theappropriate aryl substituent) was made using the corresponding phenol(8.9 g) and NaH (1.8 g) in 1:1 DNF/THF (50 mL). This solution was cooledto −78° C. and the chloridate solution was added dropwise underanhydrous conditions. After 2 hrs, the reaction mixture was quenchedwith acetic acid (5 eq) and the solvents were evaporated under vacuum.The crude mixture was partitioned between water and CH₂Cl₂. The organiclayer was concentrated and the residue was purified on a silica gelcolumn (elution with 5%-10% MeOH in CH₂Cl₂) to get the cyclic arylcompound as a single diastereomer in approximately 60% yield. Thismethod is suitable for all substituted or unsubstituted R³¹ groups,especially-aryl, subject of course to conventional protection of labilegroups other than amino for which reaction is undesired (amino isprotected by reaction with DMF and deprotected with acetic acid andalkanol treatment). This method offers the advantages of producingsubstantially stereochemically pure product, superior yield and ease ofsynthesis.

EXAMPLE 12 cHPMPC Esters

To a stirred suspension of cyclic HPMFC (1 mmol) was addedN,N′-dicyclohexyl-4-morpholinecarboxamidine (2 mmol) followed by thecorresponding acyloxymethyl chloride (1.5 mmol). The reaction wasstirred for 3 days and the DMF was evaporated under reduced pressure.The crude was purified-on a silica gel column (eluted with 5% methanolin methylene chloride) to get the pure cyclic HPMPC derivatives(approximately 30% yield).

The final product was obtained in higher yield by the same reactionusing cyclic HPMPC (1 mmol), N,N′-dicydohexyl4-morpholine-carboxamidine(1.1 mmol) followed by the corresponding acyloxymethyl chloride (1.2mmol). N⁴-benzoyl cHPMPC pivaloyloxymethyl ester was synthesized in asimilar manner using N⁴-benzoyl cHPMPC as the starting material.

EXAMPLE 13 cHPMPC Esters

cHPMPC esters were synthesized using appropriate reactants essentiallyas described in Example 11 for ester moieties corresponding to structurenumbers 6, 7, 11, 12, 13, 23, 24, 25 and 26 in Table 5A. cHPMPC esterswere synthesized using approrpiate reactants essentially as described inExample 12 for ester moieties corresponding to structure numbers 8, 9,10, 16 and 17 in Table 5A. Melting point data for cHPMPC esters ofcompound numbers 6, 8, 9, 11, 24, 25 and 26 was as follows: cHPMPC3-pyridyl ester (#6)—268-273° C. (decomposes); cHPMPC N-ethylmorpholinoester (#7)—241° C.; cHPMPC —CH₂—O—C(O)—C₆H₅ ester (#8)—198-201° C.;cHPMPC #9 ortho ester—176° C.; cHPMPC #11 ester—100-250° C.(decomposes); CHPMPC phenyl ester (#12)—190° C.; cHPMPC #24ester—218-225° C. (waxy liquid); cHPMPC #25 ester—171° C; cHPMPC #26ester—181° C.

EXAMPLE 14 9-[2,3-dideoxy-23-didehydro-4-phosphonomethoxy-β-D-erythrofuranosyl]adenine esters

Compounds where Z is of structure V and R²⁵ and R²⁹ is oxygen weresynthesized by addition-elimination reaction using

where B was adenine with iodine (2 equivalents) in acetonitrile and acompound having the structure (R³⁵O)₂P(O)—CH₂—OH (where R³⁵ wasisopropyl, phenyl or 2ethoxyphenyl) to yield the 3-iodophosphonatediester,

which was then eliminated to yield the corresponding structure Vcompound by reaction with 5 equivalents of sodium methoxide or DBU inanhydrous organic solvent such as methanol or tetrahydrofuran at roomtemperature for 12 hours.

Corresponding compounds where R²⁹ is sulfur, are synthesized by the samemethod using (R³⁵O)₂P(O)—CH₂—SH as a reactant. The compound of structure(R³⁵O)₂P(O)—CH₂—OH where R³⁵ is isopropyl has been described (KlugeOrganic Synthesis (1986) 64:80-83).

Compounds of structure (R³⁵O)₂P(O)—CH₂—OH where R³⁵ was phenyl or2ethoxyphenyl were obtained by reaction of 1 equivalent of PCl₃ with 1equivalent of t-butanol at 55° C. to obtain (R³⁵O)₂P(O)H (U.S. Pat. No.3,329,742). (R³⁵O)₂P(O)H was then silylated using 1 equivalent ofbis(trimethylsilyl)trifluoroacetamide and the resulting (R³⁵O)₂P(OTMS)was dried under vacuum. (R³⁵O)₂P(OTMS) was then converted to(R³⁵O)₂P(O)—CH₂—OH by reaction in paraformaldehyde containing catalyticamounts of titanium isopropoxide (or another lewis acid such as titaniumtetrachloride and the like can be used) for 12 hrs (12-16 hours) at 70°C. (65 to 75° C.). The 2-ethoxyphenyl product was isolated bycrystallization. The bis-phenyl product was isolated by silica gelchromatography.

bis(2-ethoxyphenyl) D4AMPI ester: ¹H-NMR (300 MHz, CDCL₃) δ 8.38 (s,1H), 7.97 (s, 1H), 7.21-6.82 (m, 9H), 6.40 (d, 1H, J=5.7 Hz), 6.30 (d,1H, J=5.8 Hz), 6.16 (s, 1H), 5.61 (s, 2H), 4.48 (dd, 1H, J=14, 8.8Hz),4.38 (dd, 1H, J=14, 6.5 Hz), 4.10-3.93 (m, 4H), 1.38 (t, 3H, J=7.1 Hz),1.35 (t, 3H, J=7.1 Hz); ³¹P-NMR (121 MHz, CDCL₃) δ 14.6.

bis(phenyl) D4AMPI ester: ¹H-NMR (300 MHz, CDCL₃) δ 8.38 (s, 1H), 7.93(s, 1H), 7.34-7.10 (m, 10H), 7.03 (s, 1H), 6.42 (d, 1H, J=5.6 Hz), 6.34(d, 1H, J=5.6 Hz), 5.98 (s, 1H), 5.83 (s, 2H), 4.32 (dd, 1H, J=14, 6.5Hz), 4.19 (dd, 1H, J=14, 6.5 Hz); ³¹P-NMR (121 MHz, CDCL₃) δ 6 13.3.

(C₆H₄(OC₂H₅)—O)₂P(O)—CH₂—OH: ¹H-NMR (300 MHz, CDCL₃) δ 7.36-7.16 (m,10H), 4.19 (dd, 2H, J=6.7, 5.9 Hz), OH not detected; ³¹P-NMR (121 MHz,CDCL₃) δ 17.0.

(C₆H₅—O)₂P(O)—CH₂—OH: ¹H-NMR (300 MHz, CDCL₃) δ 7.25-6.89 (m, 8H), 4.24(d, 2H, J=5.01 Hz), 4.18-4.08 (m, 4H), 1.46 (t, 6H, J=7.0 Hz); ³¹P-NMR(121 MHz, CDCL₃) δ 19.9.

EXAMPLE 14 N⁴-benzoyl cHPMPC

The title compound was synthesized using N⁴-benzoyl HPMPC diethyl estertritylated at the hydroxyl group as a starting material. The startingmaterial was detritylated using acetic acid and then converted toN⁴-benzoyl HPMPC using TMSBr. The resulting compound was converted toN⁴-benzoyl cHPMPC using DCC and morpholine in pyridine. The titlecompound was tested for activity against HCMV in tissue culture (NHDFcell line) and was found to be active with an IC₅₀ of 22 μM comparedwith 0.4 μM for HPMPC.

¹HNMR (300 MHz, CDCL₃) δ 8.02 (H₆, 1H, d, 7.2 Hz), 7.97 (aromatic, 2H,d, 7.2 Hz), 7.62 (aromatic, 1H, t, 7.2 Hz), 7.5 (aromatic, 2H, t, 7.2Hz), 7.26 (H₅, 1H, d, 7.2 Hz), 4.28 (1H, t, 14.7 Hz), 4.15 (1H, t, 10.8Hz), 4.0 (m, 3H), 3.84(1H,m), 2.49 (1H, d, 14.1 Hz); ³¹P-NMR (121 MHz,CDCL₃) δ 10.07. Melting point 243-246° C.

The claims shall be construed to exclude any-subject matter that, at thedate of the invention, would not have been patentable under applicablestatutory and judicial authority.

1. A compound having the structure

wherein L² and L¹ independently are —NH—CH(CH₃)—C(O)—OR⁴, Z is—O—CH_(2—CH) ₂ B is guanin-9-yl and R⁴ is H, propyl, isopropyl, t-butyl,phenyl, benzyl, 1-pyridinyl, 1-pyrimindinyl, N-ethylmorpholino,methoxyethyl, 4-hydroxy-N-methylpiperidinyl,3-hydroxy-N-methylpiperidinyl, 1-ethylpiperazinyl.
 2. A compound havingthe structure

wherein L² is —NH—CH₂—C(O)—OR⁴, L¹ is —NH—CH(CH₃)—C(O)—OR⁴, Z is—CH₂—O—CH₂—CH₂—B is adenin-9-yl and R⁴ is propyl, isopropyl, t-butyl,phenyl, benzyl, 1-pyridinyl, 1pyrimidinyl, N-ethylmorpholino,methoxyethyl, 4-hydroxy-N-methylpiperidinyl,3hydroxyl-N-methylpiperidinyl or 1-ethylpiperazinyl.